Process for producing 3-amino-2-oxo-1-halogenopropane derivatives

ABSTRACT

Compounds formed by reacting a protected amino acid with an alkali metal enolate of an alkyl acetate are reacted with a halogenating agent for halogenation of the 2-position, or a protected amino acid is reacted with an alkali metal enolate of an alkyl halogenoacetate, to form a 4-amino-3-oxo-2-halogenobutanoic acid ester derivative, and hydrolysis and decarboxylation are conducted to produce a 3-amino-2-oxo-1-halogenopropane derivative or its salt. The present method is a useful process for producing a 3-amino-2-oxo-1-halogenopropane derivatives which can easily be converted to a 3-amino-1,2-epoxypropane.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a process for producing3-amino-2-oxo-1-halogenopropane derivatives which can easily beconverted to optically active 3-substituted-3-amino-1,2-epoxypropanederivatives which are equivalents of α-aminoalcohol derivatives that areimportant as intermediates for HIV protease inhibitors or certain enzymeinhibitors.

2. Discussion of the Background

α-Aminoalcohol derivatives which can easily be converted from opticallyactive 3-substituted-3-amino-1,2-epoxypropane derivatives are used asintermediates for synthesis of a large number of HIV protease inhibitorssuch as Ro31-8959 (Parkes K. et al (Roche), J. Org. Chem., 1994, vol.59, p.3656) SC-52151 (Getman D. P. et al. (Monsanto), J. Med. Chem.,1993, Vol. 36, p. 288) VX478 (Verte, WO9405639), and AG1343 (Lilly,WO9521164].

Known examples of a method of producing 3-amino-1, 2-epoxypropanederivatives include a method in which the 2-position of anN-protected-3-amino-2-oxo-1-halogenopropane is reduced stereoselectivelyto form the corresponding alcohol, and this alcohol is then epoxidizedthrough dehydrohalogenation (Getman D. P. et al., J. Med. Chem., 1993,vol. 36, p. 288), a method in which N-protected-3-amino-1-propene isepoxidized oxidatively asymmetrically (Luly J. R. et al., J. Org. Chem.,1987, vol. 52, p. 1487), and a method in which methylene is insertedinto N-protected-3-amino-1-propanal (Searle G. D., WO93/23388.).

In the first method, it is important how the key intermediateN-protected 3-amino-2-oxo-1-halogenopropane or its equivalent substancecan be produced industrially at low cost. However, industrialization ofthis method is limited since it has to use diazomthane having quite ahigh explosiveness and a strong toxicity as a sub-starting material (seefor example, Getman D. P. et al., J. Med. Chem., 1993, vol. 36, p. 288;Okada Y. et al., Chem. Pharm. Bull., 1988 vol. 36, p. 4794; EP 346867;EP 346847; and Raddatz P. et al., J. Med. Chem., 1991, vol. 34, p.3267). Further, there is a method in which an N-substituted amino acidester is reacted with a halomethyl anion. However, quite an unstablehalomethyl anion is used, and a halogen to be introduced into the1-position is presumably limited to chorine or fluorine in view of acommon chemical knowledge. For these reasons, industrialization of thismethod is limited (Barluenga et al., J. Chem. Soc., Chem. Commun.,1994).

Still further, a method in which, after a C-terminus of an N-substitutedamino acid is activated, the resulting compound is reacted withfluoromalonic acid half ester for decarboxylation (EP 442754) can bementioned as a known technology. In this method, however, the halogen islimited to a specific element, fluorine. Therefore, this method cannotbe applied to a system containing chlorine or bromine for achieving theobject of the present invention.

In the second method, the Wittier reaction of a costly aldehyde(3-amino-1-propanal) is utilized to produce the key intermediate.N-substituted-3-amino-1-propane. Consequently, this method involvesquite a high cost. Further, in the third method, not only does themethod of forming the intermediate. N-substituted aldehyde entail a highcost, but also carbine has to be formed at a low temperature wheninserting methylene. Accordingly, this method is not industriallyappropriate.

Thus, there remains a need for a method of preparing compounds which caneasily be converted to intermediates useful for preparing HIV proteases.There also remains a need for a need for processes for preparingamino-2-oxo-1-halogenopropane derivatives and 3-amino-1,2-epoxypropanederivatives.

SUMMARY OF THE INVENTION

Accordingly, it is one object of the present invention to provide anovel process for preparing compounds which can be easily converted intoα-aminoalcohol derivatives.

It is another object of the present invention to provide a novel processfor preparing compounds which can easily be converted into3-amino-1,2-epoxypropane derivatives.

It is another object of the present invention to provide a novel processfor preparing 3-amino-1,2-epoxypropane derivatives.

It is another object of the present invention to provide a novel processfor preparing 3-amino-2-oxo-1-halogenopropane derivatives.

It is another object of the present invention to provide an industrialprocess for producing a 3-amino-2-oxo-1-halogenopropane derivative whichcan easily be converted to a 3-amino-1,2-epoxypropane derivative.

It is another object of the present invention to provide novelintermediates useful for preparing such 3-amino-2-oxo-1-halogenopropanederivatives.

These and other objects, which will become apparent during the followingdetailed description, have been achieved by the inventors' discoverythat a 3-amino-1,2-epoxypropane derivative or its equivalent substancecan be produced from the corresponding 3-amino-2-oxo-1-halogenopropanein a high yield. The inventors have also discovered its precursor, anovel α-halogeno-β-keto ester derivative and a process for producing thesame.

Thus, the present invention provides a process for producing a3-amino-2-oxo-1-halogenopropane derivative represented by formula (V)

wherein:

-   -   R_(s) represents hydrogen, an optionally substituted alkyl group        having from 1 to 10 carbon atoms, an optionally substituted aryl        group having from 6 to 15 carbon atoms, an optionally        substituted aralkyl group having from 7 to 20 carbon atoms, or        the above-mentioned groups containing a hetero atom in the        carbon skeleton; P₁ and P₂, independently from each other,        represent hydrogen or an amino-protecting group, or P₁ and P₂        together form a difunctional amino-protecting group, and at        least one of P₁ and P₂ is not hydrogen; and X represents a        halogen atom other than fluorine; or its salt.        which comprises:    -   (i) reacting a compound represented by formula (I)        wherein    -   R_(s), P₁, and P₂ and X are as defined above; and E₁ represents,        as an active carboxy terminus, an alkoxy ester residue having        from 1 to 10 carbon atoms, a phenoxy or benzyloxy group which        may have a substituent on the ring, an active ester residue of        N-oxysuccinimide or 1-oxybenzotriazole, an active thioester        residue, an imidazolyl group or a residue capable of forming an        acid halide, an acid anhydride or an acid azido,    -   with an alkali metal enolate of on acetate, to obtain a compound        represented by formula (II)        wherein    -   R_(s), P₁ and P₂ are as defined above, and R₁ represents an        optionally substituted alkyl group having from 1 to 10 carbon        atoms, an optionally substituted aryl group having from 6 to 15        carbon atoms, an optionally substituted aralkyl group having        from 7 to 20 carbon atoms, a trialkylsilyl group having from 4        to 20 carbon atoms, a phenyldialkylsilyl group having 8 to 10        carbon atoms or a diphenylalkylsilyl group having 13 to 15        carbon atoms;    -   (ii) reacting the compound of formula (II) with a halogenating        agent for halogenation of the 2-position to form a        4-amino-3-oxo-2-halogenobutanoic acid ester derivative        represented by formula (III)        wherein R_(s), P₁, P₂, X, and R₁ are as defined above;    -   (iii) further hydrolyzing the resulting compound of formula        (III), to obtain a hydrolyzate; and    -   (iv) decarboxylating the hydrolyzate, to obtain the compound of        formula (V).

The present invention also provides a process for producing a3-amino-2-oxo-1-halogenopropane derivative represented by formula (V)

wherein

-   -   R_(s), P₁, P₂, and X are as defined above, or its salt,        which comprises:    -   (i) reacting a compound represented by formula (I)        wherein    -   R_(s), P₁, P₂, and E₁ are as defined above,    -   with an alkali metal enolate or dianon of a compound represented        by formula (IV)        wherein X is as defined above, and R₂ represents hydrogen, an        optionally substituted alkyl group having from 1 to 10 carbon        atoms, an optionally substituted aryl group having from 6 to 15        carbon atoms, an optionally substituted aralkyl group having        from 7 to 20 carbon atoms, a trialkylsilyl group having from 3        to 10 carbon atoms, a phenyldialkylsilyl group having 8 to 10        carbon atoms or a diphenylalkylsilyl group having 13 to 15        carbon atoms, to form the 4-amino-3-oxo-2-halogenobutanoic acid        ester or a salt derivative represented by formula (III′)        wherein R_(s), P₁, P₂, and X are as defined above, and R₃        represents an alkali metal, an optionally substituted alkyl        group having from 1 to 10 carbon atoms, an optionally        substituted aryl group having from 6 to 15 carbon atoms, an        optionally substituted aralkyl group having from 7 to 20 carbon        atoms, a trialkylsilyl group having from 3 to 10 carbon atoms, a        phenyldialkylsilyl group having 8 to 10 carbon atoms, or        diphenylalkylsilyl group having 13 to 15 carbon atoms; and    -   (ii) further hydrolyzing the resulting compound of formula        (III), to obtain a hydrolyzate; and    -   (iii) decarboxylating the hydrolyzate, to obtain the compound of        formula (V).

The present invention also provides the 4-amino-3-oxo-2-halogenobutanoicacid ester or salt derivative of formula (III′) or its salt which is anintermediate for the production of the compound of formula (V).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The compound of formula (I) which is used in the present invention is anatural or artificial protected α-amino acid in which an amino group isprotected with a protecting group and a carboxyl group is converted to afunctional group which can be reacted with a nucleophilic agent.

The compound of formula (I) has an optical activity owing to the stearicconfiguration of the carbon atom at the root of an amino acid. Forexample, when an optically active amino acid is selected as a startingmaterial, it can easily be used in the synthesis of the desired compoundhaving an optical activity. Thus, when R_(s) is not hydrogen, theconfiguration at the carbon bearing R_(s) can be either S or R or amixture thereof. In a preferred embodiment, the configuration of thecarbon bearing R_(s) is the same as that in the α-carbon of a naturalα-amino acid.

R_(s) in formula (I) is hydrogen or an ordinary substituent such asalkyl, aryl or aralkyl. For example, when it is a methyl group, acompound having an alanine-like structure is formed. When it is a benzylgroup, a compound having a phenylalanine-like structure is formed. P₁and P₂ are ordinary amino-protecting groups. Either P₁ and P₂ may be ahydrogen atom, or P₁ and P₂ together form a difunctionalamino-protecting group. Examples thereof include benzyloxycarbonyl,tert-butoxycarbonyl, acetyl, formyl, benzoyl, dibenzyl, and phthaloyl.P₁, and P₂ may be selected in consideration of the selectivity for thefunctional group in the hydrolysis and the decarboxylation of the estergroup (R₁) which will be described later. E₁ is a functional group of acarboxy terminal which can be reacted with a nucleophillic agent.Examples thereof include lower ester residues, active ester residues,acid halide residues and acid anhydride residues. Examples, thereofinclude methoxy, ethoxy, benzoxy, substituted benzoxy, phenoxy,substituted phenoxy, N-oxysuccinimide, 1-oxybenzotriazole, imidazolyl,chlorine, bromine, methoxycarboxy, isobutoxy-carboxy andtert-butylcarboxy.

Specific examples of the compound of formula (I) includeN-benzyloxycarbonyl-L-phenylalanine methyl ester,N-benzyloxycarbonyl-L-phenylalanine-N-oxysuccinimide ester,N,N-dibenzyl-L-phenylalanine-p-nitrophenyl ester andN-benzyloxycarbonyl-S-phenyl-L-cysteine methyl ester.

The compound of formula (I) can be formed by protecting an amino groupof a natural or artificial α-amino acid by a method which is ordinarilyused in synthesis of a peptide, and then esterifying or halogenating thecarboxyl group by a method which is ordinarily used in synthesis of apeptide.

The conversion of the compound of formula (I) to the compound of formula(II) is a reaction in which the ester, the acid halide or the acidanhydride of formula (I) is reacted with an acetate enolate derived froman acetic acid ester to form the β-keto ester. The acetate enolaterefers to an alkali metal salt, and a lithium salt is most-preferable.This enolate is formed by adding an acetic acid ester to a solution of abase such as lithium amide, lithium diisopropylamide or lithiumtert-butoxide. The ester of the acetic acid ester refers to a carboxylicacid ester which is ordinarily used. Examples thereof include an alkylester, an aralkyl ester and a silyl ester. Specifically, a hydrolyzableester of methyl, ethyl, tert-butyl, benzyl or triethylsilyl isavailable.

The acetate enolate has to be used in an amount of at least 1 equivalentbased on the substrate (I). Since 1 equivalent of the base is used toform the β-keto ester enolate of the product, the reaction proceeds wellwhen at least 2 equivalents of the acetate enolate is used.

This reaction rapidly proceeds at a temperature of from −100° C. to roomtemperature. The optimum temperature varies depending on the compound.Typically, the reaction is completed at a temperature −75° C. to −300°C. for from 5 to 60 minutes. Suitable reaction solvents to be usedinclude hydrocarbons or ethers. Specific examples of the reactionsolvent include tetrahydrofuran, hexane, toluene and a mixture thereof.The reaction concentration is not particularly limited, and it may bedetermined depending on the solubility of the reaction product.

After the completion of the reaction, the reaction solution is treatedwith an acid to protonate the alkali metal salt of the product and givethe β-keto ester of formula (II). This compound can be purified throughsilica-gel chromatography. However, the compound in an unpurified statecan also be used as a starting material in the subsequent reaction.

The conversion from the compound of formula (II) to the compound offormula (III) is a reaction in which a hydrogen of the active methylenein the β-keto ester of formula (II) is oxidatively halogenated withvarious halogenating agents to obtain the4-amino-3-oxo-2-halogenobutanoic acid ester derivative of formula (III).The reaction easily proceeds only by mixing the β-keto ester with thehalogenating agent in a solvent.

The halogenating agent may be N-bromosuccinimide, copper (II) bromide orbromine in the case of bromination, and N-chlorosuccinimide, copper (II)chloride, sulfuryl chloride or chlorine in the case of chlorination. Thehalogenating agent has to be used in an amount of a theoreticalequivalent or more based on the β-keto ester of formula (II). When theamount is set exactly at the theoretical equivalent in order to proventside reactions, the most preferable yield can be provided in many cases.The theoretical equiavlent refers to an amount which is required fromthe chemical equation. For example, the amount of N-bromosuccinimide is1 equivalent based on the β-keto ester, and that of copper (II) bromideis 2 equivalents.

The reaction conditions strongly depend on the structure of the reactionproduct or the reagents, and have to be determined depending on thecompounds. For example, when R_(s) is benzyl, P₁ is benzyloxycarbonyl,P₂ is hydrogen, R₁, is tert-butyl and N-bromosuccinimide is used as areagent, the reaction is conducted at a temperature of from −20° C. toroom temperature for from 10 to 60 minutes. The reaction solventincludes halogen solvents such as methylene chloride and chloroform,ethyl acetate, ether and toluene. The reaction concentration is notparticularly limited, and may be determined depending on the solubilityof the reaction product.

The reaction product can be purified through recrystallization or thelike as required. However, the reaction product in the unpurified statecan be used as a starting material in the subsequent reaction. Adiastereomer is formed depending on the selectivity during thehalogenation. It can be separated through thin-layer chromatography orsilica-gel column chromatography. However, the separation is notrequired in view of the purpose of the process in the present invention.

The compound of formula (III), it's trimethylsilyl ester and it's acidsalt which are the compound of formula (III′) can also be obtained byreacting the compound of formula (I) with a halongenated enolate or adianion of halogenoacetic acid. That is, as stated above, when formingthe compound of formula (III′), the desired compound can be obtained inone step by using a chloracetic acid ester, a chloroacetic acid, abromoacetic acid ester or a bromoacetic acid of formula (VI) instead ofan acetic acid ester used in the method that undergoes formation of thecompound of formula (II).

In this reaction, when an enolate which is prepared from trimethylsilylhalogenoacetate or the dianion which is prepared from halogenoaceticacid are used, a product of formula (III′) (R₃ is trimethylsilyl oralkaline metal) can be converted to a compound of formula (V) withdecarboxylation by treating an acid solution in one step.

The halogenoacetate enolate can be formed by a method in which anenolate is formed by the method that undergoes formation of the compoundof formula (II). The conditions under which this enolate is reacted withthe compound of formula (I) are the same as the above-mentionedconditions.

Since the stability of the halogenoacetate enolate is inferior to thatof the acetate enolate, the reaction has to be conducted at a lowtemperature of −60° C. or less.

It may be selected as required whether the compound of formula (III′) isconverted from the compound of formula (I) directly or through formationof the compound of formula (II), because the yield varies with theidentity of the substituents or the protecting groups of the compound offormula (I).

The compound of formula (III′) is a novel compound which is anintermediate that is important in the present invention. The structureof this compound may be viewed as containing the corresponding enolsubstance as a convertible isomer. As the convertible isomer, forexample, a 4-amino-3-oxo-2-halogenobutanoic acid ester derivativerepresented by formula (VIII) can be mentioned.

wherein

-   -   R_(s) represents a hydrogen, an optionally substituted alkyl        group having from 1 to 10 carbon atoms, an optionally        substituted aryl group having from 6 to 15 carbon atoms, an        optionally substituted aralkyl group having from 7 to 20 carbon        atoms, or the above-mentioned groups containing a hetero atom        (such as O or N) in the carbon skeleton; P₁ and P₂,        independently from each other, represent hydrogen or an        amino-protecting group, or P₁ and P₂ together form a        difunctional amino-protecting group, and at least one of P₁ and        P₂ is not hydrogen; and R_(1 or 3) represents an alkali metal an        optionally substituted alkyl group having from 1 to 10 carbon        atoms, an optionally substituted aryl group having from 6 to 15        carbon atoms, an optionally substituted aralkyl group having        from 7 to 20 carbon atoms, a trialkylsilyl group having from 3        to 10 carbon atoms, a phenyldialkylsilyl group having 8 to 10        carbon atoms or a diphenylalkylsilyl group having 13 to 15        carbon atoms.

The compound of formula (III) or (III′) is converted to the compound offormula (V) by hydrolyzing the 4-amino-3-oxo-2-halogenobutanoic acidester derivative, and decarboxylating the hydrolyzate at the same time.

The hydroxylysis may be conducted by a method which is conventionallyemployed in organic chemistry. Examples of such a hydrolysis includealkali hydrolysis of a lower alkyl ester, acid hydrolysis of a tertiaryalkyl ester, catalytic hydrogenation of a benzyl ester and hydrolysis ofa silyl ester under weakly acidic to neutral conditions. However, it isrequired that the halogen introduced under such hydrolysis conditions isnot influenced. The optimum conditions vary with the structure of thecompound. The hydrolysis using a system of a tertiary alkyl ester or asilyl ester gives good results in many cases.

The desired product can be extracted and isolated from the reactionsolution to the organic solvent and can be purified with silica-gelchromatography, recrystallization, or the like.

The typical reaction conditions are that when R₁, is tert-butyl, thereaction is conducted in a formic acid solution for from a few hours toscores of hours at room temperature. The reaction time can be decreasedto from a few minutes to 1 hour by increasing the reaction temperature.The reaction concentration is not particularly limited and may bedetermined depending on the solubility of the reaction product.

The 3-amino-2-oxo-1-halogenopropane derivative of formula (V) obtainedby these methods is, as described in the literature (see for example,Getman D. P. et al., J. Med. Chem., 1993, vol. 36, p. 288; Okada Y. etal., Chem. Pharm. Bull., 1988, vol. 36, p. 4794; EP 346867; and RaddatzP. et al., J. Med. Chem., 1991, vol. 34, p. 3267), a known compoundwhich is useful as an intermediate for the synthesis of a HIV proteaseinhibitor. It is known that the above-mentioned compound is formed intoan intermediate of a more advanced form by undergoing an existingreaction in two stages as schematically shown below (Getman D. P. etal., J. Med. Chem. 1993, vol. 36, p. 288).

That is, it is possible that the 3-amino-2-oxo-1-halogenopropanederivative of formula (V) having a halogenomethyl ketone skeleton isconverted into a halohydrin represented by formula (VI) through areductive reaction of a carbonyl group

wherein R_(s), P₁, P₂, and X are as defined above and this compound isfurther easily epoxidized under alkaline conditions to form a compoundof formula (VII)

wherein R_(s), P₁, and P₂ are as defined above.

In the above-mentioned reductive reaction of the carbonyl group, thebinding stearic configuration of the substituent indicated by R_(s) inthe 3-position can be subjected to the stereoselective reduction. It canbe achieved using a common reducing agent typified by sodiumborohydride. For example, when a compound in which R_(s) is a benzylgroup, the stearic configuration in the 3-position is theS-configuration, and an urethane-type protecting group is selected as anamino-protecting group, is reduced with sodium borohydride, the stearicconfiguration of at the carbon bearing the resulting hydroxyl group ispreferentially the S-configuration in a ratio of from 2:1 to 20:1, andpurification can be conducted through recrystallization. Further, theresulting alcohol is converted to a (2S, 3S) epoxy compound which isimportant as an intermediate for a HIV protease inhibitor.

In the above-given descriptions of the compounds of formulae (I)-(VII),the substituents R_(s), R₁, R₂, R₃, and E₁ are defined in terms ofoptionally substituted alkyl groups, optionally substituted aryl groups,optionally substituted aralkyl groups, and phenoxy of benzyloxy groupswith substituted rings. Suitable substituents for these groups include,halogen, such as F, Cl, Br, and I; nitrogen-containing substituents,such as —NO₂, —NH₂, —NHR, —NRR′, and —N₃; sulfur-containingsubstituents, such as —SH, —SR, —S(O)R, and —S(O)₂R;phosphorus-containing substituents, such as —PRR′ and —P(O)RR′; andoxygen-containing substituents, such as —OH, —OR, —OCOR, and —COOR(wherein R and R′ are alkyl groups, e.g. C₁₋₄ alkyl groups).

The conversion of the starting compound of formula (I) to the desiredcompound of formula (V) and the epoxy compound of formula (VII) isschematically shown below.

wherein R_(s), R₁, R₂, R₃, E₁, X, P₁, and P₂ are as defined.

EXAMPLES

The present invention is illustrated more specifically by referring tothe following Examples. However, the present invention is not limitedthereto. The temperature is given in centigrade unless otherwisespecified. Unless otherwise indicated, all “%” values are % by weight,and all solvent ratios are by volume. Proton nuclear magnetic resonance(NMR) spectra were recorded on a Varian 300 MHz spectrometer. Chemicalshifts (γ) are given in ppm. The abbreviations used in Examples are asfollows:

-   Boc: tert-butoxycarhonyl-   Z: benzyloxycarbonyl-   THF: tetrahydrofuran-   LDA: lithium diisopropylamide-   NCS: N-chlorosuccinimide-   NBS: N-bromosuccinimide

Production Example 1

Production of N,N-dibenzyl-L-phenylalanine benzyl ester (Ia)

Twenty-five grams (151.3 mmol) of (L)-phenylalanine and 66.67 g (482.4mmol) of potassium carbonate were dissolved in 100 ml of water, and57.51 g (454.3 mmol) of benzyl chloride were added thereto. The mixturewas heat-stirred at 95° C. for 19 hours. After the reaction mixture wascooled to room temperature, 67 ml of n-heptane and 50 ml of water wereadded thereto. The organic layer was washed twice with 50 ml of amixture of methanol and water at a volume ratio of 1:2 and was thendried over anhydrous sodium sulfate. The dried substance was filteredand concentrated to give 61.64 g (90%, 121.8 mmol) of theabove-mentioned compound (Ia) in a yield of 84.7%.

¹H-NMR(300 MHz, CDCl₃) δ:3.00 (dd,1H), 3.14(dd,1H),3.53(d,2H),3.71(t,1H),3.92(d,2H),5.12(d,1H),5.23(d,1H),6.99-7.40(m,20H); Mass spectrum (FAB) 436(MH+)

Production Example 2

Production of N,N-dibenzyl-L-phenylalanine p-nitrophenyl ester (1b)

N,N-dibenzyl-L-phenylalanine hydrochloride (7.64 g, 20.0 mmol) was addedto 50 ml of chloroform, and 20.0 ml of 10% aqueous ammonia were addeddropwise to the suspension for neutralization. The organic layer wasseparated, washed with 20 ml of water, then dried over magnesiumsulfate, and filtered. The filtrate was concentrated, the resultingresidue was dissolved in 50 ml of chloroform, and 2.89 g (20.4 mmol) ofp-nitrophenol and 4.13 g (20.0 mmol) of N,N′-dicyclohexylcarbodiimidewere added to the solution in this order while being cooled with ice.The mixture was reacted overnight. To the reaction solution were added30 ml of ethyl acetate, and the N,N′-dicyclohexylurea which precipitatedwas removed by filtration. The filtrate was washed with a 10% potassiumcarbonate aqueous solution. The organic layer was separated, andconcentrated. The resulting residue was redissolved in 30 ml of ethylacetate, and the insoluble materials which precipitated were removed byfiltration. The filtrate was concentrated, and the resulting crudeproduct was purified through silica-gel column chromatography to obtain7.77 g (16.65 mmol) of the above-mentioned compound (Ib).

¹HNMR(300 MHz, CDCl₃) δ:3.13(dd,J=7.4,13.7 Hz,1H), 3.26(dd,J=8.2,13.9Hz,1H), 3.72(d,J=14.0 Hz,2H),3.96(dd, J=7.4,8.2 Hz,1H), 4.06(d,J=14.0Hz,2H), 7.14(d,J=9.2 Hz,2H), 7.06-7.37(m,15H), 8.26(d,J=9.3 Hz,2H); Massspectrum (FAB) 467(MH+)

Example 1

Production of (4S)-4-(N,N-dibenzylamino)-4-benzyl-3-oxobutanoic acidtert-butyl ester (IIa)

A solution (2.0M) (24 ml, 48 mmol) of LDA in heptane, THF and ethylbenzene was dissolved in 64 ml of anhydrous THF, and the mixed solutionwas cooled to −53° C. in an argon atmosphere. To this solution was addeddropwise a solution of 5.8 g (50 mmols) of tert-butyl acetate in 12 mlof THF for approximately 15 minutes, while maintaining the temperatureof from −45° C. to −50° C. After the completion of the dropwiseaddition, the mixture was stirred at −53° C. for 1 hour. Subsequently, asolution of 7.2 g (15 mmols, purity 90%) of N,N-dibenzyl-L-phenylalaninebenzyl ester (Ia) in 8 ml of THF was added dropwise thereto forapproximately 15 minutes while maintaining the temperature at from −48°C. to −52° C. After the completion of the dropwise addition, thereaction temperature was raised to −5° C. After three hours, a solutionof 16.5 g of citric acid in 50 ml of water was added to the reactionsolution to stop the reaction. The resulting mixture was extracted twicewith ethyl acetate (100 ml and 50 ml), and the organic layer was washedwith 20 ml of 10% citric acid, with 10 ml of a saturated aqueoussolution of sodium chloride, with 5% sodium hydrogencarbonate aqueoussolution (20 ml×4) and with 10 ml of a saturated aqueous solution ofsodium chloride in this order. The organic layer was dried overanhydrous magnesium sulfate, and the filtrate was concentrated. Theconcentrate was purified through silica-gel column chromatography(eluent-mixture of n-hexane and ethyl acetate at a ratio of 4:1) to give6.09 g (13.7 mmol) of the above-mentioned compound (IIa).

¹HNMR(300 MHz, CDCl₃) δ:1.25(s,9H), 2.93(dd,J=3.9, 13.5 Hz,1H),3.20(dd,J=9.0,13.5 Hz,1H), 3.40(d,J=15.6 Hz,2H), 3.55(m,2H),3.62(dd,J=3.9,9.0 Hz,1H), 3.82(d,J=13.5 Hz,2H), 7.10-7.38 (m,15H); Massspectrum (Fa-B) 444(MH+)

Example 2

Production of (4S)-4-(N-benzyloxycarbonyl)amino-4-benzyl-3-oxobutanoicacid tert-butyl ester (IIb)

A solution (2.0M)(14 ml, 28 mmol) of LDA in heptane, THF and ethylbenzene was dissolved in 30 ml of anhydrous THF in an argon atmosphere,and the mixed solution was cooled to −45° C. To this solution was addeddropwise a solution of 3.7 g (32 mmol) of tert-butyl acetate in 4 ml ofTHF for approximately 15 minutes while maintaining the temperature atfrom −40° C. to −45° C. After the completion of the dropwise addition,the resulting solution was stirred at −50° C. for 30 minutes, and asolution of 2.5 g (8 mmol) of N-benzyloxycarbonyl-L-phenylalanine methylester (Ic) was added dropwise thereto for approximately 10 minutes whilemaintaining the temperature at from −40° C. to −45° C. After thecompletion of the dropwise addition, the reaction solution was stirredat −40° C. for 30 minutes, then heated to 0° C. and stirred for 20minutes. Forty milliliters of a 20% citric acid aqueous solution wereadded to the reaction solution to stop the reaction. The mixture wasextracted with ethyl acetate (50 ml×2), and the organic layer was washedwith 5 ml of water, with 20 ml of a 5% sodium hydrogencarbonate aqueoussolution and with 10 ml of water in this order. The resulting organiclayer was dried over anhydrous magnesium sulfate, and the filtrate wasconcentrated. The concentrate was purified through silica-gel columnchromatography (eluent- mixture of n-hexane and ethyl acetate at a ratioof 4:1) to give 3.08 g (7.77 mmol) of the above-mentioned compound(IIb).

¹HNMR(300 MHz, CDCl₃) δ: 1.44 (s,9H), 2.99 (dd,J=7.1,14.1 Hz,1H),3.17(dd,J=6.1,14.1 Hz,1H), 3.38(m,2H), 4.68(bq,J=approx. 7,1H),5.07(s,2H), 5.38(bd,J=7.9 Hz,1H), 7.12-7.35(m,10H);

¹³CNMR(75 MHz, CDCl₃) δ: 28.0, 37.1, 48.2, 60.7, 67.0, 82.4, 127.1,128.1, 128.2, 128.5, 128.7, 129.2, 135.8, 137.9, 165.8, 182.0, 201.7;Mass spectrum (FAB) 398(MH+)

Example 3

Production of (4S)-4-(N-benzyloxycarbonyl)amino-4-benzyl-3-oxobutanoicacid ethyl ester (IIc)

A solution (2.0M) (4 ml, mmol) of LDA in heptane, THF and ethyl benzenewas dissolved in 8 ml of anhydrous THF in an argon atmosphere, and themixed solution was cooled to −50° C. To this solution was added dropwisea solution of 740 mg (8 mmol) of ethyl acetate in 2 ml of THF forapproximately 5 minutes while maintaining the temperature at from −50°C. to −45° C. After the completion of the dropwise addition, the mixturewas stirred at −50° C. for 30 minutes, and a solution of 626 mg (2 mmol)of N-benzyloxycarbonyl-L-phenylalanine methyl ester (Ic) in 2 ml of THFwas further added to the above-mentioned solution for approximately 5minutes while maintaining the temperature at from −50° C. to −45° C.After the completion of the dropwise addition, the reaction solution wasstirred at −50° C. for 30 minutes, the temperature was then raised toroom temperature, and the mixture was stirred for 5 minutes. Tenmilliliters of a 10% citric acid aqueous solution was added to thereaction solution to stop the reaction. The reaction mixture wasextracted with ethyl acetate. The organic layer was passed through asilica-gel column, and then concentrated to give 826 mg of theabove-mentioned compound (IIc) as a crude oil.

¹HNMR(300 MHz, CDCl₃) δ: 1.22-1.30 (m,3H), 2.92-3.05 (m,1H),3.05-3.22(m,1H), 3.40-3.54(m,2H), 4.10-4.19(m,2H), 4.66(m,1H),5.07(bs,2H), 5,55(bd,J=7.8 Hz,1H), 7.11-7.38(m,10H)

Example 4

Production of (4S)-4-(N-tert-butoxycarbonyl)amino-4-benzyl-3-oxobutanoicacid tert-butyl ester (IId)

A solution (2.0M)(27 ml, 54 mmol) of LDA in heptane, THF and ethylbenzene was dissolved in 50 ml of anhydrous THF in an argon atmosphere,and the mixed solution was cooled to −45° C. To this solution was addeddropwise a solution of 7.0 g (60 mmols) of tert-butyl acetate in 5 ml ofTHF for approximately 20 minutes while maintaining the temperature atfrom −40° C. to −45° C. After the completion of the dropwise addition,the mixture was stirred at −50° C. for 30 minutes. To this solution wasadded dropwise a solution of 4.18 g (15 mmols) ofN-tert-butoxycarbonyl-L-phenylalanine methyl ester (Id) in 5 ml of THFfor approximately 20 minutes while maintaining the temperature of from−40° C. to −45° C. After the completion of the dropwise addition, thereaction solution was stirred at −50° C. for 30 minutes, and 40 ml of a25% citric acid aqueous solution were added to the reaction solution tostop the reaction. After the organic solvent in the reaction solutionwas distilled off under reduced pressure, the residue was extracted with100 ml of ethyl acetate, and the organic layer was washed with 20 ml ofwater. This organic layer was concentrated and passed through asilica-gel column (eluent: mixture of n-hexane and ethyl acetate at avolume ratio of 4:1) to give 5.92 g of crystals. The NMR analysis of thecrystals revealed the above-mentioned compound (IId) containing 15% ofthe unreacted starting compound (Id).

¹HNMR(300 MHz, CDCl₃) δ: 1.39(s,9H), 1.46(s,9H), 2.96(dd,J=7.4,14.0Hz,1H), 3.16(dd,J=5.7,14.0 Hz,1H), 3.34-3.45(m,2H), 4.57(bq,j=approx.6.Hz,1H), 5.09(bd,J=7.7 Hz,1H), 7.11-7.30(m,5H);

¹³CNMR(75 MHz, CDCl₃) δ: 27.8, 28.2, 36.9, 48.0, 60.4, 80.0, 82.0,126.9, 128.4, 129.2, 136.2, 155.1, 166.0, 202.2

Example 5

Production of (4S)-4-(N,N-dibenzylamino)-4-benzyl-3-oxo-2-bromobutanoicacid tert-butyl ester (IIIa)

(1) Finely divided copper (II) bromide (0.45 g, 2.0 mmol) was dissolvedin 2 ml of ethyl acetate. A solution obtained by dissolving 0.44 g (1.0mmol) of the compound (IIa) obtained in Example 1 and 0.14 ml (1.0 mmol)of triethylamine in 2 ml of ethyl acetate was added thereto at 25° C.while being stirred. After the reaction was conducted at 25° C. for 36hours in an argon atmosphere, 5 milliliters of a 5 citric acid aqueoussolution were added to the mixture to separate the organic layer. Thisorganic layer was concentrated to give 0.45 g (0.86 mmol) of an isomermixture of the above-mentioned compound (IIIA) as brown crystals.

¹HNMR (300 MHz, CDCl₃) (isomer mixture) δ: 0.90 (s,9/2H), 1.44(s,9/2H),2.99(dd,J=3.7,13.5 Hz,1H), 3.14-3.29(m,1H), 3.50(dd,J=5.6,13.3 Hz,2H),3.83(dd,J=10.3,13.3 Hz,2H), 3.82(dd,1/2H), 4.03(dd,3.7,9.5,1/2H),5.42(s,1/2H), 5.51(s,1/2H), 7.14-7.34(m, 15H); Mass spectrum (ESI)522.3, 524.3(MH+)

(2) The compound (IIa) (0.89 g, 2.0 mmols) obtained in Example I wasdissolved in 10 ml of diethyl ether. NBS (0.39 g, 2.0 mmol) was addedthereto while being stirred with ice cooling, and the mixture wasfurther stirred for 2 hours. After the reaction was further conducted atroom temperature for 13 hours, 5 ml of water were added to the reactionmixture to separate the organic layer. The organic layer wasconcentrated to give 1.23 g of brown crystals. The NMR analysis of thecrystals revealed that approximately 35% of the starting compound (IIa)still remained and the main product was an isomer mixture of theabove-mentioned compound (IIIa).

Example 6

Production of(4S)-4-(N-benzyloxycarbonyl)amino-4-benzyl-3-oxo-2-chlorobutanoic acidtert-butyl ester (IIIb)

The compound (IIb) (0.8 g, 2.0 mmols) obtained in Example 2 wasdissolved in 5 ml of chloroform. NCS (264 mg, 1.98 mmol) was addedthereto while being stirred with ice cooling, and the mixture wasfurther stirred for 3 hours while being cooled with ice. Two millilitersof water were added to the reaction solution to separate the organiclayer. This organic layer was concentrated to give 912 mg of crystals.One hundred milligrams of a part of the crystals were eluted throughsilica-gel thin-layer chromatography (eluent: mixture of n-hexane andethyl acetate at a ratio of 4:1) to give 40 mg of an isomer mixture ofthe abovementioned compound (IIIb).

¹HNMR (300 MHz, CDCl₃) (isomer mixture) δ 1.45-1.48 (m, 9H), 2.95-3.05(m,1H), 3.18-3.38(m,1H), 4.85-5.10(m, 4H), 5.20-5.3 5(m,1H),7.14-7.35(m,10H);

Example 7

Production of(4S)-4-(N-benzyloxycarbonyl)amino-4-benzyl-3-oxo-2-bromobutanoic acidtert-butyl ester (IIIc)

The compound (IIb) (0.8 g, 2.0 mmol) obtained in Example 2 was dissolvedin 5 ml of chloroform. NBS (338 mg, 1.9 mmols) was added thereto whilebeing stirred with ice cooling, and the mixture was further stirred for30 minutes while being cooled with ice. Three milliliters of water wereadded to the reaction solution to separate the organic layer. Thisorganic layer was concentrated to give 921 mg of an isomer mixture ofthe above-mentioned compound (IIIC) as crude light brown crystals.

¹HNMR(300 MHz, CDCl₃) (isomer mixture) δ1.43-1.50 (m,9H),3.00(dd,J=7.4,14.1 Hz,1H), 3.21(dd,J=5.7,14.1 Hz,1H), 4.82-5.03(m,1H),4.89(bs,1H), 5.07(bs,2H), 5.20 (bd,J=6.0 Hz,1H), 7.17-7.35(m, 10H); Massspectrum (FAD) 476,478(MH+)

Example 8

Production of (3S)-3-(N,N-dibenzyl)amino-3-benzyl-2-oxo-1-bromopropane(Va)

The compound (IIIA) (41 mg, 0.078 mmols) obtained in Example 5 wasdissolved in 4N hydrogen chloride (ethyl acetate solution, 1 ml) Themixture was stirred at room temperature for 13 hours for reaction. Threemilliliters of ethyl acetate were added to the reaction solution, andwere neutralized with a saturated aqueous solution of sodiumhydrogencarbonate. The organic layer was concentrated to give 30 mg ofthe above-mentioned crude compound (Va).

¹HNMR(300 MHz, CDCl₃) δ: 3.00(dd,J=3.9,13.5 Hz,1H), 3.25 (dd,J=9.0,13.5,Hz,1H), 3.55(d,J=15.6 Hz,2H), 3.67(dd,J=3.9,9.0 Hz,1H), 3.84(d,J=15.6Hz,2H), 4.42(s, 1H),4.48(s,1H), 7.10-7.38(m,15H)

Example 9

Production of(3S)-3-(N-benzyloxycarbonyl)amino-3-benzyl-2-oxo-1-chloropropane (Vb)

The compound (IIb) (3S g, 88 mmol) obtained in Example 2 was dissolvedin 88 ml of methylene chloride. Sulfuryl chloride (7.23 ml, 90 mmol) wasadded thereto while being stirred with ice cooling. The mixture wasstirred for 1 hour while being cooled with ice and further at roomtemperature for 30 minutes. The reaction solution was concentrated togive 37 g of the crude compound (IIIB) as crystals. The crystals (35 g)were suspended in 80 ml of formic acid (purity 90%). The suspension washeated at 80° C. while being stirred, and was reacted for 30 minutes.The reaction solution was cooled, and formic acid was distilled offunder reduced pressure to obtain the above-mentioned compound (Vb) ascrystals. Further, the crystals were recrystallized from 200 ml ofisopropanol, and were dried to give 19.55 g of the above-mentionedcompound (Vb).

¹H-NMR(300 MHz, CDCl₃) δ: 3.05 (dd, J=7.2,14.0 Hz,1H)3.25(dd,J=7.1,14.0, Hz,1H), 3.97(d,J=16.2 Hz,1H), 4.14(d,J=16.2 Hz,1H),4.77(q,J=4.77 Hz,2H), 5.08(s,2H), 5.29(d,J=7.2 Hz,1H),7.12-7.35 (m,10H);

¹³C-NMR(75 MHz, CDCl₃) δ: 37.8, 47.4, 58.7, 67.3, 127.5, 128.1, 128.3,128.6, 129.0, 129.1, 135.2, 135.9, 155.7, 201.0

Example 10

Production of(3S)-3-(N-benzyloxycarbonylamino)-3-benzyl-2-oxo-1-bromopropane (Vc)

(1) The compound (IIIC) (56 mg, 0.12 mmol) obtained in Example 7 wasdissolved in 1 ml of methylene chloride, and 0.3 ml of trifluoroaceticacid were added thereto. The mixture was stirred at 60° C. for 17 hoursfor reaction. The reaction solution was neutralized with a saturatedaqueous solution of sodium hydrogencarbonate, and was extracted withethyl acetate. The organic layer was concentrated, and then elutedthrough silica-gel thin-layer chromatography (eluent: mixture ofn-hexane and ethyl acetate at a ratio of 4:1) to give 20 mg of theabove-mentioned compound (Vc).

¹HNMR,(300 MHz, CDCl₃) δ: 3.06(dd,J=7.2,13.9 Hz,1H), 3.09(dd,J=6.9,13.9Hz,1H), 3.81(d,J=13.7 Hz,1H), 3.93(d,J=13.7 Hz,1H), 4.82(bq,J=7.3Hz,1H), 4.89(bs,1H), 5.08(bs,2H), 5.34(bd,J=7.2 Hz,1H),7.13-7.39(m,10H);

¹³CNMR(75 MHz, CDCl₃) δ: 33.1, 37.7, 58.8, 67.2, 127.3, 128.0, 128.3,128.5, 128.9, 129.1, 135.5, 136.0, 155.8, 200.4; Mass spectrum (ESI)376(MH+)

(2) The compound (IIIC) (360 mg, 0.756 mmol) was dissolved 2 ml offormic acid, and the solution was stirred at 25° C. for 15 hours forreaction. After formic acid was distilled off under reduced pressure,the concentrate was neutralized with a 5% sodium hydrogencarbonateaqueous solution, and was extracted with ethyl acetate. The organiclayer was concentrated to give 296 mg of the compound (Vc) as crudecrystals. Further, the crystals were eluted through silica-gelthin-layer chromatography (eluent: mixture of n-hexane and ethyl acetateat a ratio of 4:1) to give 149 g of the purified crystals of theabove-mentioned compound (Vc).

Example 11

Production of(3S)-3-(N-benzyloxycarbonyl)amino-3-benzyl-2-hydroxy-1-chloropropane(VIb)

The compound (Vb) (136 mg, 0.4 mmol) obtained in Example 9 was dissolvedin 1.5 ml of methanol. To this solution were added 17 mg (0.44 mmols) ofsodium borohydride at 0° C., and the mixture was stirred at 0° C. for 2hours for reaction. To the reaction solution was added 1N hydrochloricacid to stop the reaction. Then, methanol was distilled off underreduced pressure. This solution was extracted with ethyl acetate, andthe organic layer was concentrated to give 138 mg of the mixture of theabove-mentioned compounds (2S, 3S)-(VIb) and (2R, 3S)-(VIb) at a ratioof 74:26 as light yellow crystals.

¹HNMR(300 MHz, CDCl₃) (diastereomer mixture) δ: 2.93(dd,J=8.4,14.0Hz,1H), 3.00(dd,J=4.9,14.0 Hz,1H), 3.50-3.60(m,1H), 3.65(dd,J=4.2,12.0Hz,1H), 3.81-3.89(m, 1H),3.92-4.03(m,1H), 4.87(bd,J=approx.8 Hz,1H),5.03(bs, 2H), 7.17-7.37(m,10H)

Example 12

Production of(3S)-3-(N-benzyloxycarbonyl)amino-3-benzyl-2-hydroxy-1-bromopropane(VIc)

The compound (Vc) (142 mg, 0.37 mmol) obtained in Example 10 wasdissolved in a mixed solvent containing 3 ml of methanol and 1 ml ofTHF. To this solution were added 16 mg (0.41 mmol) of sodium borohydrideat 0° C., and the mixture was stirred at from 0° C. to 5° C. for 2hours. To the reaction solution were added 2 ml of 1N hydrochloric acidto stop the reaction. Then, methanol and THF were distilled off underreduced pressure. The thus-obtained slurry was extracted with ethylacetate, and the organic layer was concentrated to give 146 mg of themixture of the above-mentioned compounds (2S, 3S)-(VIc) and (2R,3S)-(VIc) at a ratio of 84:16 as light yellow crystals.

¹HNMR(300 MHz, CDCl₃) (diastereomer mixture) δ: 2.90(dd,J=9.7,14.0Hz,1H), 2.99(dd,J=4.7,14.0 Hz,1H), 3.38-3.47 (m,1H), 3.53(dd,J=3.6,10.6Hz,1H), 3.81-3.90 (m,1H), 3.93-4.03(m,1H), 4.86(bd,J=approx.8 Hz,1H),5.03 (s,2H), 7.16-7.35(m,10H)

Example 13

Production of(3S)-3-(N-benzyloxycarbonyl)amino-3-benzyl-1,2-epoxypropane (VIIb)

(1) One hundred milligrams (0.3 mmol) of the mixture of the compounds(2S, 3S)-(VIb) and (2R, 3S)-(VIc) (at a ratio of approximately 3:1)obtained in Example 11 were dissolved in 2 ml of THF. To this solutionwere added 40 mg (0.27 mmol) of potassium tert-butoxide at −10° C., andthe mixture was stirred at −10° C. for 15 minutes for reaction. Thereaction solution was extracted with 3 ml of water and with 10 ml ofmethylene chloride to separate the organic layer. This organic layer wasconcentrated. The resulting crystals were purified through silica-gelthin-layer chromatography (mixture of n-hexane and ethyl acetate at aratio of 2:1) to give 20 mg of the mixture of the above-mentionedcompounds (2S, 3S)-(VIIb) and (2R, 3S)-(VIIb)(at a ratio ofapproximately 3:1).

¹HNMR(300 MHz, CDCl₃) (diastereomer mixture) δ:2.52-2.58(m,2/4H,(2R,3S)), 2.71-2.80(m,6/4H,(2S,3S)), 2.83-2.95(m,1H),2.99(dd,J=5.0,14.2 Hz,1H), 3.69-3.72(m, 1H,3/4H,(2S,3S)),4.12-4.25(m,1H,1/4H,(2R,3S)), 4.67-4.80(m,1H), 5.03(s,6/4H, (2S,3S)),5.05(s,2/4H,(2R, 3S)), 7.18-7.35(m,10H)

(2) The mixture (164 mg) of the compounds (2S, 3S)-(VIc) and (2R,3S)-(VIc) (at a ratio of approximately 5:1) obtained in Example 12 wasdissolved in 4.5 ml of methanol. To this solution were added 58 mg (0.41mmols) of potassium carbonate at room temperature, and the mixture wasfurther stirred at room temperature for 1 hour for reaction. Thereaction solution was extracted with 3 ml of 1N hydrochloric acid andwith 10 ml of ethyl acetate to separate the organic layer. This organiclayer was concentrated. The resulting crystals were purified throughsilica-gel thin-layer chromatography (mixture of n-hexane and ethylacetate at a ratio of 2:1) to give 79 mg of the mixture of theabove-mentioned compounds (2S, 3S)-(VIIb) and (2R, 3S)-(VIIb) (at aratio of approximately 5:1) as white crystals.

Example 14

Production of (4S)-4-(N,N-dibenzyl)amino-4-benzyl-3-oxo-2-chlorobutanoicacid tert-butyl ester (IIId)

Anhydrous THF (3.2 ml) was mixed with 2.0M (0.39 ml, 0.78 mmol) of asolution of LDA in heptane, THF and ethyl benzene in an argonatmosphere, and the mixture was cooled to −70° C. To this solution wereadded dropwise 0.13 ml (0.85 mmol) of tert-butyl chloroacetate (IVa).After the mixture was stirred, for 30 minutes, a solution of 154 mg(0.34 mmol) of the compound (Ib) in 1.0 ml of anhydrous THF was addedthereto dropwise. While the temperature was gradually raised, themixture was stirred for 3 hours. After this, the reaction solution washeated to room temperature, 3.0 mg of a 10% citric acid aqueous solutionand 10 ml of ethyl acetate were added thereto in this order to extractthe reaction mixture. The organic layer was washed with 10 ml of water,dried over magnesium sulfate, and filtered. The filtrate wasconcentrated, and the resulting crude product was purified throughsilica-gel thin-layer chromatography to give 200.2 mg of the mixture ofthe above-mentioned compounds (2S, 4S)-(IIID) and (2R, 4S)-(IIID). Thediastereomer ratio was approximately 2:1 as calculated from the ¹H-NMRintegration ratio.

¹HNMR (300 MHz, CDCl₃) (diastereomer mixture) δ: 0.86 (s,6H),1.44(s,3H), 2.94-3.04(m,1H), 3.17(dd,J=9.8, 13.4 Hz,1/3H),3.26(dd,J=9.8,13.3 Hz,2/3H), 3.50(d,J=13.2 Hz,4/3H), 3.51(d,J=13.2Hz,2/3H), 3.81(d,J=13.2 Hz,4/3H) 3.85(d,J=13.1 Hz,2/3H),3.87(dd,J=3.0,9.7 Hz,2/3H), 4.00 (dd,J=3.0,9.7 Hz,1/3H), 5.37(s,1/3H),5.48(s,2/3H), 7.08-7.39(m,15H); Mass spectrum (FAB) 478(MH+)

Example 15

Production of (4S)-4-(N-benzyloxycarbonyl)amino-4-benzyl-3-oxo-butanoicacid tert-butyl ester (IIb)

A solution (2.0M) (231 ml, 462 mmol) of LDA in heptane, THF andethylbenzene was dissolved in 400 ml of anhydrous THF in argonatmosphere, and the mixed solution was cooled to −50° C. To thissolution was added dropwise a solution of 58.1g (500 mmol) of tert-butylacetate in 40 ml of THF for approximately 40 minutes while maintainingthe temperature at −45° C. to −50° C. After the completion of thedropwise addition, the mixture was stirred at −45° C. for 30 minutes. Tothis solution was added dropwise a solution of 39.4 g (125 mmol) ofN-benzyloxycarbonyl-L-phenylalanine methyl ester (Ic) in 40 ml of THFfor approximately 30 minutes while maintaining the temperature at −45°C. to −50° C. After the completion of the dropwise addition, thereaction solution was stirred at −45° C. for 1 hour, and 500 ml of 2Nhydrochloric acid and 150 g of ice were added to the reaction solutionto stop the reaction. The temperature was then raised to roomtemperature, and the organic layer was separated. The water layer wasextracted with 350 ml of toluene, and the organic layers were combined.The organic layer was washed with 50 ml of 5% sodium hydrogencarbonateaqueous solution and 50 ml of 25% sodium chloride aqueous solution inthat order. The organic layer was dried over anhydrous magnesiumsulfate, and the filtrate was concentrated to give 58.1 g (86.4 wt %,126 mmol) of the above-mentioned crude compound.

Example 16

Production of(4S)-(N-benzyloxycarbonyl)amino-4-benzyl-3-oxo-2-chlorobutanoic acidtert-butyl ester (IIIb)

40.5 (86.4 wt %, 88 mmol) of(4S)-4-(N-benzyloxycarbonyl)amino-4-benzyl-3-oxo-butanoic acid tertbutylester (IIb) was dissolved in 88 ml of dichloromethane. 7.23 ml (90 mmol)of sulfuryl chloride was added thereto while being stirred with icecooling, and the mixture was further stirred for 1 hour with ice coolingand for 30 minutes at room temperature. The reaction mixture wasconcentrated under reduced pressure below 30° C. to give 48.6 g of theabove-mentioned crude compound as crystals. 2 g of the crude product wasrecrystallized from 10 ml of toluene to give the purified crystals.(main isomer)

¹H-NMR (300 MHz, CDCl₃) δ: 1.44(s,9H), 2.99(dd,J=7.5,14.1 Hz,1H),3.20(dd,J=6.1,14.1 Hz, 1H), 4.85(s,1H), 4.97(br.q,J=8.4 Hz,1H),5.60(s,2H), 5.25(br.d,J=8.4 Hz,1H), 7.1-7.3S(m,10H);

¹³C-NMR (75 MHz, CDCl₃) δ: 27.5, 37.7, 59.5, 60.0, 67.2, 85.0, 127.3,128.1, 128.3, 128.5, 128.9, 129.2, 135.3, 136.0, 155.6, 163.1, 197.4;Mass spectrum (FAB) 432 (MH+) 454(MNa+)

Example 17

Production of(3S)-(N-benzyloxycarbonyl)amino-3-benzyl-2-oxo-1-chloropropane (Vb)

46.6 g of crude crystals of (4S)-4-(N-benzyloxycarbonyl)amino-4-benzyl-3-oxo-2-chlorobutanoic acid tert-butyl ester (IIIB)obtained in Example 16 was suspended in 80 ml of formic acid (90%), andthe mixture was stirred for 20 minutes at 80° C. This reaction mixturewas concentrated under reduced pressure to give the above-mentionedcompound as crude crystals.

The crude crystals were dissolved in 200 ml of 2-propanol at 60° C., andcooled to 5° C. The resulting crystals were collected by filtration andwashed with 50 ml of 2-propanol. The crystals obtained were dried underreduced pressure to give 20.1 g (60 mmol) of the above-mentionedcompound.

Example 18

Production of(2S,3S)-3-(N-benzyloxycarbonyl)amino-3-benzyl-2-hydroxy-1-chloropropane(VIb)

17.0 g (51.2 mmol) of (3S)-3-(N-benzyloxycarbonyl)amino-3-benzyl-2-oxo-1-chloropronane (Vb) was dissolved in a mixedsolvent containing 180 ml of dichloromethane and 180 ml of methanol.2.03 g (53.8 mmol) of sodium borohydride was added portionwise theretoat 0° C. for 10 minutes, and the mixture was further stirred for 30minutes at 0° C. 12.9 ml (226 mmol) of acetic acid was added to thereaction mixture, and the mixture was concentrated under reducedpressure to remove methanol. 50 ml of water was added thereto, and theresulting mixture was extracted twice with dichloromethane (150 ml and50 ml). The combined organic layer was concentrated to give the mixtureof above-mentioned compound and the diastereomer

((2R,3S)-form) (at ratio of approximately 84:16) as white crystals.

1 g of these crystals was recrystallized from 15 ml of a mixed solventcontaining ethyl acetate and hexane (at a ratio of 5:1) to give 0.6 g(97%d.e.) of the above-mentioned compound.

((2S, 3S)-form)

¹H-NMR (300 MHz, CDCl₃) δ: 2.87(dd,J=9.0,14.1 Hz,1H), 3.00(dd,J=4.6,14.1Hz,1H), 3.55(dd,J=7.3,11.3 Hz,1H), 3.60(br.s,1H), 3.62 (dd,J=4.3,11.3Hz,1H), 3.86 (br.q, J=approx 5 Hz, 1H), 3.96-4.06(m,1H), 5.01(s,2H),5.31(br.d,J=approx. 8.5 Hz,1H), 7.18-7.33 (m,10H);

¹³C-NMR (75 MHz, CDCl₃) δ: 35.3, 47.1, 54.6, 66.5, 73.2, 126.4, 127.8,127.9, 128.3, 128.3, 129.3, 136.3, 137.5, 156.0; Mass spectrum (ESI)334.2 (MH+) 356.2 (MNa+) 689.3 (2MNa+)

Example 19

Production of(2S-3S)-3-(N-benzyloxycarbonyl)amino-3-benzyl-1,2-epoxypropane (VIIb)

The crude diastereomeric mixture of3-(N-benzyloxycarbonyl)amino-3-benzyl-2-hydroxy-1-chloropropane (VIb)obtained in Example 18 ((2S,3S)-(VIb) and (2R,3S)-(VIb) at a ratio of84:16) was dissolved in 600 ml of methanol. To this solution was added14.1 g (102 mmol) of potassium carbonate at room temperature, and themixture was further stirred at room temperature for 3 hours forreaction. After the insoluble matter of the reaction mixture was removedby filtration and washed with 20 ml of methanol, the filtrate wasconcentrated to approximately 100 ml under reduced pressure below 35° C.The resulting mixture was acidified with 100 ml of 0.5N hydrochloricacid, and was extracted twice with dichloromethane (150 ml and 150 ml).The organic layer was concentrated under 40° C. to give 14.0 g (47.1mmol) of the mixture of the above-mentioned compound and itsdiastereomer (2R,3S)-(VIIb) (at a ratio of 84:16) as white crystals.

The crystals obtained was recrystallized from 6 ml of a mixed solventcontaining ethyl acetate and hexane (at a ratio of 1:1) to give 0.58 g(97%de) of the above-mentioned compound.

((2S,3S)-form)

¹H-NMR (300 MHz, CDCl₃) δ: 2.71-2.80(m,2H), 2.85 (dd,J=8.1,14.1 Hz,1H),2.91(dd,J=2.7,6.4 Hz,1H), 2.98(dd,J=S.1,14.1 Hz,1H), 3.68-3.82(m,1H),4.77(br.d,J=5.9 Hz,1H), 5.03(s,2H), 7.17-7.33(m,10H);

¹³C-NMR (75 MHz, CDCl₃) δ:37.5, 46.7, 53.0, 53.2, 66.8, 126.8, 128.0,128.1, 128.5, 128.6, 129.3, 136.2, 136.4, 155.7; Mass spectrum (ESI)298.2(MH+), 320.2(MNa+), 336.3 (MK+), 617.5 (2MNa+).

Example 20

Production of(2R3S)-3-(N-benzyloxycarbonyl)amino-2-hydroxy-1-(N-isobutyl)amino-4-phenylbutane(IXa)

4.47 g (15.0 mmol) of the diastereomeric mixture of3(N-benzyloxycarbonyl)amino-3-benzyl-1,2-epoxypropane (VIIb) obtained inExample 19 ((2S, 3S)-(VIIb) and (2R, 3S)-(VIIb) at a ratio of 84:16) wassuspended in 29 ml of ethanol. To this suspension was added 22.4 ml (225mmol) of isobutylamine, and the mixture was stirred at 70° C. for 1 hourfor reaction. The reaction solution was concentrated to give the mixtureof the above-mentioned compound and its diastereomer (2S,3S)-(VIIIa) (ata ratio of 84:16) as white crystals.

The titled compound (2R,3S)-(VIIIa) was prepared substantially inaccordance with the above-mentioned procedure, using the (2S,3S)-(VIIb).

(2R, 3S)-form)

¹H-NMR (300 MHz, CDCl₃) δ: 0.90 (d, J=6.6 Hz, 6H), 1.60-1.80 (m,1H),2.38 (d,J=6.8 Hz, 2H), 2.65 (dd, J=6.8, 12.4 Hz,1H), 2.70 (dd, J=4.0,12.4 Hz, 1H), 2.70 (br.s,1H), 2.86 (dd, J=8.1, 14.1 Hz, 1H), 2.99 (dd,J=4.8, 14.1 Hz, 1H), 3.49 (br.q, J=approx 4.5 Hz, 1H), 3.80-3.95 (m,1H), 5.02 (s, 2H), 5.11 (br.d, J=9.0 Hz, 1H), 7.19-7.32 (m, 10H);

¹³C-NMR (75 MHz, CDCl₃) δ: 20.5, 28.3, 36.6, 51.4, 55.0, 57.9, 66.5,70.4, 126.4, 127.8, 128.0, 128.4, 128.4, 129.5, 136.6, 137.7, 156.3;Mass spectrum (ESI) 371.2 (MH+)

Example 21

Production of 4-Nitro-N-((2′R(syn),3′S)-3-(N-benzyloxycarbonyl)amino-2′-hydroxy-4′-phenylbutyl)-N-isobutyl-benzenesulfonamide(IXb)

6.08 g (15.0 mmol) the diastereomeric mixture of3-(N-benzyloxycarbonyl)amino-2-hydroxy-1-(N-isobutyl)amino-4-phenylbutane (IXa) obtained in Example 20 ((2R, 3S)-(IXa) and(2S,3S)-(IXa) at a ratio of 84:16) was dissolved in 40 ml ofdichloromethane. To this solution were added 2.55 g (24.1 mmol) ofsodium carbonate in 20 ml of water, and 4.0 g (18.0 mmol) of4-nitrobenzenesulfonylchloride in 5 ml of dichloromethane was addeddropwise thereto with ice cooling over 10 minutes. After the reactionmixture was further stirred for 3 hours, the organic layer wasseparated. The resulting organic layer was concentrated to give themixture of the above-mentioned compound and its diastereomer(2′S,3′S)-(VIIIb) (at a ratio of 84:16) as white crystals.

These crude crystals were dissolved in 100 ml of ethanol at 70° C. Afterthe crystallization was started at 55° C., it was kept at 55° C. for 1hour and then was cooled to 20° C. The resulting crystals were collectedby filtration and washed with 30 ml of ethanol. The crystals obtainedwere dried under reduced pressure to give 6.07 g (10.9 mmol) of theabove-mentioned compound.

((2′R(syn).3′S)-form)

¹H-NMR (300 MHz, CDCl₃) δ: 0. 84 (d, J=6.1 Hz, 3H), 0.86 (d, J=6.3 Hz,3H), 1.75-1.95 (m, 1H), 2.88 (dd, J=7.5 14.1 Hz, 2H), 2.96 (d, J=6.8 Hz,2H), 3.00 (dd, J=4.7, 14.1, 1H), 2.90 (br. s, 1H), 3.12-3.26 (m, 2H),3.80-3.91 (m, 2H), 4.99 (br. d, J=8.7 Hz, 1H), 5.01 (s, 2H), 7.21-7.32(m, 10H), 7.92 (d, J=8.7 Hz, 2H), 8.29 (d, J=8.7 Hz, 2H);

¹³C-NMR, (75 MHz, CDCl₃) δ: 19.8, 19.9, 35.5, 52.4, 57.7, 66.9, 72.1,124.3, 126.7, 127.8, 128.2, 128.5, 128.5, 128.6, 129.3, 136.1, 137.2,144.6, 150.0, 156.5

Example 22

Production of 4-Nitro-N-((2′R (syn),3′S)-3′-(N-tertbutyloxycarbonyl)amino-2′-hydroxy-4′-phenylbutyl)-N-isobutyl-benzenesulfonamide(IXc)

13.0 g (23.4 mmol, 96%de) of 4-nitro-N-((2′R,(syn),3′S)-3′-(N-benzyloxycarbonyl)amino-2′-hydroxy-4′-phenylbutyl)-N-isobutyl-benzenesulfonamide(IXb) was dissolved in 77 ml of dichloromethane and 2 ml (46.8 mmol) ofmethanol. To this solution was added 19.3 ml (HBr 93.6 mmol) of 30%hydrobromic acid in acetic acid solution, and the mixture was furtherstirred at room temperature for 3 hours. The reaction solution wasneutralized with 300 ml of 10% sodium carbonate aqueous solution. Theresulting mixture was extracted with 100 ml of dichloromethane toseparate the organic layer. To this organic layer was added 5.62 g (25.7mmol) of diterbutyl dicarbonate as dissolved in 50 ml ofdichloromethane, and the mixture was stirred at room temperature for 2hours. The reaction solution was concentrated to approximately 100 ml.To the resulting solution were added 100 ml of methanol and 3.23 g (23.4mmol) of potassium carbonate, and the mixture was further stirred atroom temperature for 3 hours to remove the acetylated compound of (VIIC)at the 2-position. To the resulting mixture was added 1.34 ml (23.4mmol) of acetic acid to stop the reaction, and the mixture wasconcentrated. 50 ml of water and 200 ml of dichloromethane were added tothe mixture to separate the organic layer. The organic layer wasconcentrated to give the crude crystals of the above-mentioned compound.

These crude crystals was dissolved in 550 ml of ethanol at 55° C. Afterthe crystallization was started at 40° C., it was cooled to 5° C. Theresulting crystals were collected by filtration and washed with 100 mlof ethanol. The crystals obtained were dried under reduced pressure togive 8.71 g (16.7 mmol, 100%de) of the above-mentioned compound as whitecrystals.

((2′R(syn),3′S)-form)

¹H-NMR (300 MHz, CDCl₃) δ: 0.87 (d, J=6.6 Hz, 3H), 0.88 (d, J=6.6 Hz,3H), 1.36 (s, 9H), 1.81-1.96 (m, 1H), 2.83-2.96 (m, 2H), 2.99 (d, J=7.5Hz, 2H), 3.20 (d, J=5.3 Hz,2H), 3.70-3.85 (m, 2H), 3.82 (br.s, 1H), 4.64(br.d, J=7.6 Hz, 1H), 7.21-7.33 (m, 10H), 7.96 (d, J=8.8 Hz, 2H), 8.33(d, J=8.8 Hz, 2H);

¹³C-NMR (75 MHz, CDCl₃) δ: 19.8, 20.0, 26.9, 28.2, 35.6, 52.5, 55.2,57.5, 72.2, 80.1, 124.3, 126.6, 128.5, 128.6, 129.4, 137.5, 144.8,150.0, 156.3; Mass spectrum (ESI) 522.3 (MH+), 544.5 (MNa+), 560.4 (MK+)

Example 23

Production of N-(S)-tetrahydrofuran-3-yloxycarbonyl-L-phenylalaninemethyl ester (Ie)

0.881 g (10 mmol) of (S)-3-hydroxytetrahydrofuran was dissolved in 10 mlof dichloromethane. To this solution was added 1.34 g (4.5 mmol) oftriphosgene, and this solution was cooled to −40° C. 1.04 ml (13.5 mmol)of pyridine dissolved in 5 ml of dichloromethane was added dropwisethereto over approximately 15 minutes, and the mixture was furtherstirred at room temperature for 3.5 hours. To the resulting solution wasadded dropwise 1.94 g (9 mmol) of L-phenylalanine methyl ester hydrogenchloride dissolved to 5 ml of dichloromethane with ice cooling. And then2.12 g (20 mmol) of sodium carbonate dissolved in 20 ml of water wasadded dropwise thereto over approximately 15 minutes, and the mixturewas further stirred at room temperature for 2.5 hours. The organic layerwas separated, and was washed with 1N hydrochloric acid (10 ml×2) andwater (10 ml×1). The resulting organic layer was concentrated to give2.10 g (7.2 mmol) of the above-mentioned compound as a yellow oil.

¹H-NMR (300 MHz, CDCl₃) δ: 1.96-2.15 (m, 2H), 3.05 (dd, J=5.6, 13.9 Hz,1H), 3.13 (dd, J=6.4, 13.9 Hz, 1H), 3.72 (s, 3H), 3.75-3.91 (m, 4H),4.62 (br.q, J=approx. 6 Hz, 1H), 5.19-5.23 (m, 1H), 5.26 (br.q, J=8.7Hz, 1H), 7.10-7.29 (m, 5H);

¹³C-NMR (75 MHz, CDCl₃) δ: 32.7, 38.2, 52.3, 54.7, 66.9, 73.2, 75.5,127.1, 128.6, 129.2, 135.7, 155.3, 172.0; Mass spectrum (FAB) 294 (MH+)

Example 24

Production of(4S)-4-(N-(S)-tetrahydrofuran-3′-yloxycarbonyl)amino-5-phenyl-3-oxo-pentanoicacid tert-butyl ester (IIe)

A solution (2.0M) (9 ml, 18 mmol) of LDA in heptane, THF andethylbenzene was dissolved in 20 ml of anhydrous THF under an argonatmosphere, and the mixed solution was cooled to −50° C. To thissolution was added dropwise a solution of 2.3 g (20 mmol) of tert-butylacetate in 3 ml of THF over approximately 10 minutes while maintainingthe temperature at −45° C. to −50° C. After the completion of thedropwise addition, the mixture was stirred at −45° C. for 30 minutes. Tothis solution was added dropwise a solution of 1.75 g (5.3 mmol) ofN-(S)-tetrahydrofuran-3-yloxycarbonyl-L-phenylalanine methyl ester (Ie)in 3 ml of THF over approximately 10 minutes while maintaining thetemperature at −40° C. to −45° C. After the completion of the dropwiseaddition, the reaction solution was stirred at −45° C. for 1 hour, and2.3 ml of acetic acid was added to the reaction solution to stop thereaction. To this were added 20 ml of water and 50 ml of toluene, andthe organic layer was separated. The resulting organic layer was washedwith 10 ml of 5% sodium hydrogencarbonate aqueous solution and 10 ml ofwater in that order. The organic layer was dried over anhydrousmagnesium sulfate, and the filtrate was concentrated to give 1.95 g (52mmol) of the above-mentioned crude compound.

¹H-NMR (300 MHz, CDCl₃) δ: 1.46 (s, 9H), 1.96-2.17 (m, 2H), 2.97 (dd,J=7.3, 14.2 Hz, 1H), 3.17 (dd, J=6.2, 14.2 Hz, 1H), 3.39 (br.s, 2H),3.70-3.90 (m, 4H), 4.66 (br.q, J=approx. 6.5 Hz, 1H), 5.15-5.23 (m, 1H),5.34 (br.d, J=7.8 Hz, 1H), 7.15-7.31 (m, SH);

¹³C-NMR (75 MHz, CDCl₃) δ: 27.9, 32.7, 37.1, 48.2, 60.6, 66.9, 73.2,75.6, 82.3, 127.1, 128.7, 129.2, 135.7, 155.4, 165.8, 201.6

Example 25

Production of(4S)-4-(N-(S)-tetrahydrofuran-3′-yloxycarbonyl)amino-2-chloro-5-phenyl-3-oxo-pentanoicacid tert-butyl ester (IIIe)

1.8 g (4.7 mmol) of(4S)-4-(N-(S)-tetrahydrofuran-3′-yloxycarbonyl)amino-5-phenyl-3-oxo-pentanoicacid tert-butyl ester (IIIe) was dissolved in 5 ml of dichloromethane.0.39 ml (4.7 mmol) of sulfuryl chloride was added thereto while beingstirred with ice cooling, and the mixture was further stirred for 1 hourat room temperature. The reaction mixture was concentrated under reducedpressure below 30° C. to give the above-mentioned crude compound.

¹H-NMR (300 MHz, CDCl₃) δ: 1.40 (s, 9H), 1.96-2.17 (m, 2H), 2.92-3.02(m, 1H), 3.17-3.25 (m, 1H), 3.67-3.90 (m, 4H), 4.90 (d, J=13.5 Hz, 1H),4.98 (br.q, J=approx. 6.0 Hz, 1H), 5.15-5.19 (m, 1H), 5.27 (br.d, J=8.3Hz, 1H), 7.18-7.30 (m, 5H);

¹³C-NMR (75 MHz, CDCl₃) δ: 27.7, 32.7, 37.6, 59.1, 60.9, 66.9, 73.0,75.9, 84.8, 127.3, 128.8, 129.3, 135.3, 155.3, 163.3, 197.4

Example 26

Production of(3S)-1-chloro-2-oxo-3-(N-(S)-tetrahydrofuran-3′-yloxycarbonyl)amino-4-phenylbutane(Vd)

The crude compound of(4S)-4-(N)-(S)-tetrahydrofuran-3′-yloxycarbonyl)amino-2-chloro-5-phenyl-3-oxo-pentanoicacid tert-butyl ester (IIIe) obtained in Example 25 was dissolved in 5ml of formic acid (90%), and the mixture was stirred for 15 minutes at80° C. This reaction mixture was concentrated under reduced pressure,and to the resulting mixture was added 10 ml of 2-propanol to formcrystals. The crystals were dissolved at 60° C., and the mixture wasstirred at room temperature for 2 hours and at 5° C. for 30 minutes. Theresulting crystals were collected by filtration and were washed with 2ml of 2-propanol to give 0.854 g (2.7 mmol) of the above-mentionedcompound as white crystals.

¹H-NMR (300 MHz, CDCl₃) δ: 1.93-2.03 (m, 1H), 2.08-2.20 (m, 1H), 3.00(dd, J=7.1, 13.8 Hz, 1H), 3.10 (dd, J=6.8, 13.8 Hz, 1H), 3.75-3.92 (m,4H), 3.98 (d, J=16.2 Hz, 1H), 4.16 (d, J=16.2 Hz, 1H), 4.75 (br.q,J=approx. 7.5 Hz, 1H), 5.17-5.22 (m, 1H), 5.36 (br.d, J=7.14 Hz, 1H),5.15-5.21 (m, 1H), 7.20-7.34 (m, 5H);

¹³C-NMR (75 MHz, CDCl₃) δ: 32.7, 37.7, 47.3, 58.5, 66.9, 73.1, 75.9,127.5, 129.0, 129.0, 135.2, 155.4, 201.0

Example 27

Production of(2S,3S)-1-chloro-2-hydroxy-3-(N-(S)-tetrahydrofuran-3′-yloxycarbonyl)amino-4-phenylbutane(VId)

0.706 g (2.26 mmol) of(3S)-1-chloro-2-oxo-3-(N-(S)-tetrahydrofuran-3′-yloxycarbonyl)amino-4-phenylbutane(Vd) was dissolved in a mixed solvent containing 8 ml of dichloromethaneand 80 ml of methanol. 60 mg (1.6 mmol) of sodium borohydride was addedthereto at −3° C. for 5 minutes, and the mixture was further stirred for60 minutes at −3° C. 0.385 ml (6.72 mmol) of acetic acid was added tothe reaction mixture, and the mixture was concentrated under reducedpressure to remove methanol. 5 ml of water was added thereto, and theresulting mixture was extracted twice with dichloromethane (20 ml and 10ml). The combined organic layer was concentrated to give the mixture ofabove-mentioned compound and the diastereomer ((2R,3S)-form) (at ratioof approximately 83:17) as white crystals. (2S,3S)-form)

¹H-NMR (300 MHz, CDCl₃) δ: 1.90-2.00 (m, 1H), 2.05-2.18 (m, 1H), 2.80(dd, J=9.3, 14.0 Hz, 1H), 3.01 (dd, J=4.3, 14.0 Hz, 1H), 3.54 (br.s,1H), 3.52-3.66 (m, 2H), 3.67-3.90 (m, 5H), 3.94-4.03 (m, 1H), 5.08-5.16(m, 1H), 5.64 (br.d, J=9.4 Hz, 1H), 7.20-7.30 (m, 5H);

¹³C-NMR (75 MHz, CDCl₃) δ: 32.4, 35.1, 46.8, 54.2, 66.5, 72.9, 73.0,74.7, 126.0, 128.0, 129.1, 137.6, 155.5; Mass spectrum (ESI) 314.3 (MH+)

Example 28

Production of(2S,3S)-3-(N-(S)-tetrahydrofuran-3′-yloxycarbonyl)amino-4-phenylbutane-1,2-epoxide(VIIc)

The crude diastereomeric mixture of (2S,3S)-1-chloro-2-hydroxy-3-(N-(S)-tetrahydrofuran-3′-yloxycarbonyl)amino-4-phenylbutane(VId) obtained in Example 27 ((2S, 3S)-(VIb) and (2R,3S)-(VIb) at aratio of 83:17) was dissolved in 20 ml of methanol. To this solution wasadded 624 mg (4.52 mmol) of potassium carbonate at room temperature, andthe mixture was further stirred at room temperature for 2 hours forreaction. After the insoluble matter of the reaction mixture was removedby filtration, the filtrate was concentrated under reduced pressurebelow 35° C. The resulting mixture was acidified with 10 ml of 0.5Nhydrochloric acid and was extracted twice with dichloromethane (10 mland 10 ml). The organic layer was concentrated at 40° C. to give 0.58 g(2.1 mmol) of the mixture of the above-mentioned compound and itsdiastereomer (2R,3S)-(VIIb) (at a ratio of 83:17) as white crystals.(2S,3S)-form)

¹H-NMR (300 MHz, CDCl₃) δ: 2.72-2.78 (m, 2H), 2.78-2.83 (m, 1H),2.86-3.02 (m, 2H), 3.70-3.90 (m, 5H), 4.65-4.68 (br., 1H), 5.15-5.21 (m,1H), 7.20-7.34 (m, 5H);

¹³C-NMR (75 MHz, CDCl₃) δ: 32.7, 37.5, 46.7, 53.0, 53.0, 66.9, 73.2,75.4, 126.9, 128.7, 129.4, 136.3, 155.5; Mass spectrum (ESI) 278.2 (MH+)

Example 29

Production of(2R,3S)-3-(N-(S)-tetrahydrofuran-3′-yloxycarbonyl)amino-2-hydroxy-1-(N-isobutyl)amino-4-phenylbutane(IXd)

0.58 g (2.1 mmol) of the diastereomeric mixture of3-(N-(S)-tetrahydrofuran-3′-yloxycarbonyl)amino-4-phenylbutane-1,2-epoxide(VIIc) obtained in Example 28 ((2S,3S)-(VIIc) and (2R,3S)-(VIIc) at aratio of 83:17) was suspended in 4 ml of ethanol. To this suspension wasadded 3.4 ml (33.9 mmol) of isobutylamine, and the mixture was stirredat 70° C. for 1 hour for reaction. The reaction solution wasconcentrated to give the mixture of the above-mentioned compound and itsdiastereomer (2S,3S)-(VIIIa) (at a ratio of 83:17) as white crystals.

((2R,3S)-form)

¹H-NMR (300 MHz, CDCl₃) δ: 0.91 (d, J=6.6 Hz, 6H), 1.72 (hep, J=6.6 Hz,1H), 1.80-1.95 (m, 1H), 2.02-2.14 (m, 1H), 2.37-2.44 (m, 2H), 2.64-2.99(m, SH), 3.55-3.86 (m, SH), 5.11 (br., 1H), 5.43 (br.d, J=8.7 Hz, 1H),7.19-7.28 (m, 5H);

¹³C-NMR (75 MHz, CDCl₃) δ: 20.4, 28.2, 32.7, 36.6, 51.4, 55.2, 57.7,66.8, 70.3, 73.2, 75.0, 126.3, 128.3, 129.3, 137.7, 155.9; Mass spectrum(ESI) 351.3 (MH+)

Example 30

Production of4-Nitro-N-((2′R(syn),3′S)-2′-hydroxy-4′-phenyl-3′-(N-(S)-tetrahydrofuran-3-yloxycarbonyl)aminobutyl)-N-isobutyl-benzenesulfonamide(IXe)

The diastereomeric mixture of(2R,3S)-3-(N-(S)-tetrahydrofuran-3′-yloxycarbonyl)amino-2-hydroxy-1-(N-isobutyl)amino-4-phenylbutane(IXd) obtained in Example 29 ((2R,3S)-(IXd) and (2S,3S)-(IXd) at a ratioof 83:17) was dissolved in 2 ml of dichloromethane. To this solution wasadded 0.233 g (2.2 mmol) of sodium carbonate dissolved in 2 ml of water,and 0.488 g (2.2 mmol) of 4-nitrobenzenesulfonylchloride dissolved in 1ml of dichloromethane was added thereto with ice cooling for 2 minutes.While the reaction mixture was further stirred for 3 hours at roomtemperature, 6 ml of dichloromethane and 2 ml of water were addedthereto because it was difficult to stir the mixture owing to depositionof the crystals. The organic layer was separated and the resultingorganic layer was concentrated to give 0.974 g of the mixture of theabove-mentioned compound and its diastereomer (2′S,3′S)-(IXe) (at aratio of 83:17) as white crystals.

These crude crystals were dissolved in 60 ml of ethanol at 70° C. Afterthe crystallization was started at 55° C., it was cooled to 5° C. Theresulting crystals were filtered and washed with 5 ml of ethanol. Thecrystals obtained were dried under reduced pressure to give 0.642 g(96.4%de) of the above-mentioned compound.

This crystals was recrystallized from 50 ml of ethanol to give 0.583 gof the above-mentioned compound (100%de). ((2′R(syn),3′S)-form)

¹H-NMR (300 MHz, CDCl₃) δ: 0.87 (d, J=7.0 Hz, 3H), 0.89 (d, J=7.0 Hz,3H), 1.89 (hep, J=6.8, 1H), 1.90-1.94 (m, 1H), 2.08-2.15 (m, 1H),2.86-3.04 (m, 4H), 3.11-3.24 (m, 2H), 3.58 (br.s, 6H), 3.65-3.87 (m,6H), 4.85 (br.d, J=5.2 Hz, 1H), 5.10-5.18 (m, 1H), 7.20-7.37 (m, 5H),7.95 (d, J=8.9 Hz, 2H), 8.34 (d, J=8.9 Hz, 2H);

¹³C-NMR (75 MHz, CDCl₃) δ: 19.8, 19.9, 27.0, 32.7, 35.4, 52.7, 55.3,57.8, 66.8, 72.1, 73.1, 75.6, 124.3, 126.7, 128.5, 128.6, 129.3, 137.2,144.7, 150.0, 156.2; Mass spectrum (FAB) 536 (MH+)

Example 31

Production of(4R)-4-(N-benzyloxycarbonyl)amino-3-oxo-5-phenylthiopentanoic acidtert-butyl ester (IIf)

A solution (2.0M) (420 ml, 840 mmol) of LDA in heptane, THF andethylbenzene was dissolved in 800 ml of anhydrous THF under an argonatmosphere, and the mixed solution was cooled to −66° C. To thissolution was added dropwise a solution of 99.54 g (856.9 mmol) oftert-butyl acetate in 53 ml of THF over approximately 10 minutes whilemaintaining the temperature at −69° C. to −71° C. After the completionof the dropwise addition, the mixture was stirred at −69° C. to −74° C.for 60 minutes. To this solution was added dropwise a solution of 80.00g (231.6 mmol) of N-benzyloxycarbonyl-(S-phenyl)-L-cysteine methyl ester(If) in 135 ml of THF over approximately 45 minutes while maintainingthe temperature at −69° C. to −73° C. After the completion of thedropwise addition, the reaction solution was stirred at −69° C. to −74°C. for 2.5 hours. The reaction solution was added to 150 ml of 36%hydrochloric acid dissolved in 750 ml of water. To this was added 80 mlof ethyl acetate, and the organic layer was separated. The resultingwater layer was extracted with 550 ml of ethyl acetate. The organiclayers were combined and were washed with 300 ml of 1N hydrochloricacid, saturated sodium hydrogencarbonate aqueous solution and saturatedsodium chloride aqueous solution in that order. The organic layer wasdried over anhydrous sodium sulfate, and the filtrate was concentratedto give 108.04 g (79.9 wt %, 86.33 g) of the above-mentioned crudecompound. The yield was 86.8%.

¹H-NMR (300 MHz, CDCl₃) δ: 3.28 (dd, 1H), 3.36-3.52 (m, 3H), 4.60 (dd,1H), 5.07 (d, 1H), 5.10 (d, 1H), 5.58 (br.d, 1H), 7.19-7.40 (m, 10H);Mass spectrum (ESI) 452 (MNa+)

Example 32

Production of(3R)-3-(N-benzyloxycarbonyl)amino-1-chloro-2-oxo-4-phenylthiobutane (Ve)

108.04 g (79.9 wt %, 86.33 g, 201.0 mmol) of(4R)-4-(N-benzyloxycarbonyl)amino-3-oxo-5-phenylthiopentanoic acidtert-butyl ester (IIf) was dissolved in 320 ml of dichloromethane, andwas cooled to −32° C. 34.38 g (254.7 mmol) of sulfuryl chloridedissolved in 22 ml of dichloromethane was added dropwise thereto over 80minutes while being stirred at −32° C. to −31° C., and the mixture wasfurther stirred for 80 minutes at −32° C. to −31° C. To the reactionmixture was added 300 ml of water, and the organic layer was separated.The resulting organic layer was washed with saturated sodiumhydrgencarbonate aqueous solution and saturated sodium chloride aqueoussolution in that order, and was dried over sodium sulfate. The filtratewas concentrated, and the resulting residue was dissolved in 192 ml offormic acid (90%), and the mixture was stirred for 4 hours at 50° C. to52° C. This reaction mixture was concentrated under reduced pressure,and to the resulting mixture was added 200 ml of 2-propanol. The mixturewas concentrated again, and to the resulting mixture was added 400 ml of2-propanol to form the crystals. The crystals formed were dissolved at52° C., and the solution was cooled to 5° C. The resulting crystals werecollected by filtration and were washed with 150 ml of 2-propanol togive 51.5 g (98.0 wt %, 50.47 g) of the above-mentioned compound aswhite crystals. The yield was 59.9%.

¹H-NMR (300 MHz, CDCl₃) δ: 3.32 (dd, 1H), 3.42 (dd, 1H), 4.13 (d, 1H),4.72 (d, 1H), 4.73 (dd, 1H), 5.00 (s, 2H) 5.57 (br.d, 1H), 7.22-7.40 (m,10H); Mass spectrum (ESI) 364 (MH+)

Example 33

Production of(2R,3S)-3-(N-benzyloxycarbonyl)amino-1-chloro-2-hydroxy-4-phenylthiobutane(VIe)

51.5 g (98.0 wt %, 50.47 g, 138.7 mmol) of(3R)-3-(N-benzyloxycarbonyl)amino-1-chloro-2-oxo-4-phenylthiobutane (Ve)was dissolved in a mixed solvent containing 300 ml of dichloromethaneand 187 ml of methanol. 3.64 g (96.2 mmol) of sodium borohydride wasadded portionwise thereto at −11° C. to −9° C. over 1 hour, and themixture was further stirred for 40 minutes at −12° C. to −9° C. 48 ml of2N hydrochloric acid was added to the reaction mixture, and the mixturewas concentrated under reduced pressure to remove methanol. 500 ml ofdichloromethane and 300 ml of water were added thereto, and the organiclayer was separated. The resulting organic layer was washed with 300 mlof saturated sodium chloride aqueous solution and was dried over sodiumsulfate. The filtrate was concentrated to give the mixture ofabove-mentioned compound and the diastereomer ((2R,3S)-form) (at a ratioof approximately 83:17) as the result of the HPLC analysis.

The crude crystals were dissolved in 200 ml of ethyl acetate and 300 mlof hexane at 60° C. The solution was cooled to 5° C., and the resultingcrystals were collected by filtration and were washed with 170 ml of amixed solvent containing hexane and ethyl acetate at a ratio of 2:1 togive 38.77 g (98.6 %de) of the above-mentioned compound as whitecrystals. The yield was 76.4%.

(2R, 3 S)-form)

¹H-NMR, (300 MHz, CDCl₃) δ: 3.29 (d, 2H), 3.60 (dd, 1H), 3.68 (dd, 1H),3.88-3.96 (m, 2H), 5.07 (s, 2H), 5.15 (br., 2H), 7.18-7.39 (m, 10H)

Example 34

Production of(3S)-3-(N-benzyloxycarbonyl)amino-3-benzyl-2-oxo-1-chloropropane (Vb)

1.00 g (2.38 mmol) of N-benzyloxycarbonyl-L-phenylalanine p-nitrophenylester (Ig) and 1.45 ml (9.38 mmol) of trimethylsilyl chloroacetate (IVb)were dissolved in 10 ml of THF under an argon atmosphere, and the mixedsolution was cooled to −75° C. To this solution was added dropwise asolution (2.0M) (4.52 ml, 9.04 mmol) of LDA in heptane, THF, andethylbenzene as dissolved in 4 ml of anhydrous THF over approximately 1hour and 15 minutes while maintaining the temperature at −72° C. to −65°C. After the completion of the dropwise addition, the mixture wasstirred at −72° C. for 3 hours. 20 ml of 10% citric acid aqueoussolution was added to the reaction solution to stop the reaction. Thetemperature was then raised to room temperature, and 20 ml of ethylacetate was added. The resulting organic layer was separated and waswashed with 10 ml of water twice. The organic layer was dried overanhydrous magnesium sulfate, and the filtrate was concentrated to givethe above-mentioned crude compound. As the result of HPLC analysis, thiscrude compound contained 316.6 mg (0.954 mmol, 48.4%) of theabove-mentioned compound (Vb) and the starting materialN-benzyloxycarbonyl-L-phenylalanine p-nitrophenyl ester (Ig) 398.8 mg(0.949 mmol, 39.9%).

Example 35

Production of(3S)-3-(N-tert-butyloxycarbonyl)amino-3-benzyl-2-oxo-1-chloro-propane(Vf)

1.002 g (2.594 mmol) of N-tert-butyloxycarbonyl-L-phenylalaninep-nitrophenyl ester (Ih) and 2.04 ml (12.96 mmol) of trimethylsilylchloroacetate (IVb) were dissolved in 10 ml of THF under an argonatmosphere, and the mixed solution was cooled to −70° C. To thissolution was added dropwise a solution (2.0M) (6.47 ml, 12.95 mmol) ofLDA in heptane, THF and ethylbenzene was dissolved in 9 ml of anhydrousTHF over approximately 70 minutes while maintaining the temperature at−70° C. to −68° C. After the completion of the dropwise addition, themixture was stirred at −70° C. for 3 hours. 20 ml of 10% citric acidaqueous solution was added to the reaction solution to stop thereaction. The temperature was then raised to room temperature, and 20 mlof ethyl acetate was added. The resulting organic layer was separatedand was washed with 10 ml of water twice. The organic layer was driedover anhydrous magnesium sulfate, and the filtrate was concentrated togive the above-mentioned crude compound. As the result of HPLC analysis,this crude compound contained 413.5 mg (1.389 mmol, 53.5%) of theabove-mentioned compound (Vf) and the starting materialN-tertbutyloxycarbonyl-L-phenylalanine p-nitrophenyl ester (Ih) 164 mg(0.425 mmol, 16.4 %)

Example 36

Production of(3S)-3-(N-tert-butyloxycarbonyl)amino-3-benzyl-2-oxo-1-chloropropane(Vf)

A solution (2.0M) (4.9 ml, 9.8 mmol) of LDA in heptane, THF andethylbenzene was dissolved in 10 ml of anhydrous THF under an argonatmosphere, and the mixed solution was cooled to −75° C. To thissolution was added dropwise a solution of 463 mg (4.9 mmol) ofchloroacetic acid (IVc) in 3.5 ml of THF over approximately 20 minuteswhile maintaining the temperature at −75° C. to −70° C. After thecompletion of the dropwise addition, the mixture was stirred at −75° C.to −70° C. for 30 minutes. To this solution was added dropwise asolution of 500 mg (1.29 mmol) ofN-tert-butyloxycarbonyl-L-phenylalanine p-nitrophenyl ester (Ih) in 4 mlof THF over approximately 15 minutes while maintaining the temperatureof −75° C. to −70° C. After the completion of the dropwise addition, thereaction solution was stirred at −75° C. to −70° C. for 3 hours, and 20ml of 10% citric acid aqueous solution was added to the reactionsolution to stop the reaction. The temperature was then raised to roomtemperature, and 20 ml of ethyl acetate was added, and the resultingorganic layer was separated. The organic layer was washed with 20 ml ofsaturated sodium hydrogencarbonate aqueous solution and 20 ml ofsaturated sodium chloride aqueous solution in that order. The organiclayer was dried over anhydrous sodium sulfate, and the filtrate wasconcentrated to give the above-mentioned crude compound. As the resultof HPLC analysis, this crude compound contained 186 mg (0.625 mmol) ofthe above-mentioned compound (Vf). The yield was 48.4%.

For convenience, the compounds which were used or synthesized in theabove-mentioned Production Examples and Examples are shown below.

The present invention has made it possible to produce3-amino-2-oxo-1-halogenopropane derivatives which can easily beconverted to 3-amino-1,2-epoxypropanes that are important asintermediates for pharmaceutical preparations including HIV proteaseinhibitors and certain enzyme inhibitors, in high yields by anindustrial, safe process comprising a few steps.

This application is based on Japanese Patent Application No.299827/1995, which was filed on November 17, 1995, and which isincorporated herein by reference in its entirety.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that, within the scope of the appended claims, theinvention may be practiced otherwise than as specifically describedherein.

1. A process for producing a 3-amino-2-oxo-1-halogenopropane derivativerepresented by formula (V)

wherein R_(s) represents hydrogen, an optionally substituted alkyl grouphaving from 1 to 10 carbon atoms, an optionally substituted aryl grouphaving from 6 to 15 carbon atoms, an optionally substituted aralkylgroup having from 7 to 20 carbon atoms, or the above-mentioned groupscontaining a hetero atom in the carbon skeleton; P₁ and P₂,independently from each other, represent hydrogen or an amino-protectinggroup, or P₁ and P₂ together form a difunctional amino-protecting group,and at least one of P₁ and P₂ is not hydrogen; and X represents ahalogen atom other than fluorine or its salt, which comprises: (i)reacting a compound represented by formula (I)

wherein R_(s), P₁, and P₂ are as defined above, and E₁ represents analkoxy ester residue having from 1 to 10 carbon atoms, a phenoxy orbenzyloxy group, which may have a substituent in the ring, an esterresidue of N-oxysuccinimide or 1-oxybenzotriazole, an active thioesterresidue, an imidazolyl group or a residue capable of forming an acidhalide, an acid anhydride or an acid azido, with an alkali metal enolateof an acetate to obtain a compound represented by formula (II)

wherein R_(s), P₁, and P₂ are as defined above, and R₁ represents anoptionally substituted alkyl group having from 1 to 10 carbon atoms, anoptionally substituted aryl group having from 6 to 15 carbon atoms, anoptionally substituted aralkyl group having from 7 to 20 carbon atoms, atrialkylsilyl group having from 4 to 10 carbon atoms, aphenyldialkylsilyl group having 8 to 10 carbon atoms or adiphenylalkylsilyl group having 13 to 15 carbon atoms; (ii) reacting thecompound of formula (II) with a halogenating agent for halogenation ofthe 2-position to form a 4-amino-3-oxo-2-halogenobutanoic acid esterderivative represented by formula (III)

wherein R_(s), P₁, P₂, R₁ and X are as defined above; (iii) furtherhydrolyzing the resulting compound of formula (III), to obtain ahydrolyzate; and (iv) decarboxylating said hydrolyzate, to obtain saidcompound of formula (V).
 2. The process of claim 1, wherein the carbonatom to which R_(s) is bonded in the compound of formula (I) has aS-configuration except for a case where R_(s) in formula (I) ishydrogen.
 3. The process of claim 1, wherein the carbon atom to whichR_(s) is bonded in the compound of formula (I) has an R-configurationexcept for a case where R_(s) in formula (I) is hydrogen.
 4. A processfor producing a 3-amino-2-oxo-1-halogenopropane derivative representedby formula (V)

wherein R_(s) represents hydrogen, an optionally substituted alkyl grouphaving from 1 to 10 carbon atoms, an optionally substituted aryl grouphaving from 6 to 15 carbon atoms, an optionally substituted aralkylgroup having from 7 to 20 carbon atoms, or the above-mentioned groupscontaining a hetero atom in the carbon skeleton; P₁ and P₂,independently from each other, represent hydrogen or an amino-protectinggroup, or P₁ and P₂ together form a difunctional amino-protecting group,and at least one of P₁ and P₂ is not hydrogen; and X represents ahalogen atom other than fluorine or its salt, which comprises: (i)reacting a compound represented by formula (I)

wherein R_(s), P₁, and P₂ are as defined above, and E₁ represents analkoxy ester residue having from 1 to 10 carbon atoms, a phenoxy orbenzyloxy group, which may have a substituent in the ring, an esterresidue of N-oxysuccinimide or 1-oxybenzotriazole, an active thioesterresidue, an imidazolyl group or a residue capable of forming an acidhalide, an acid anhydride or an acid azido with an alkali metal enolateor dianion of a compound represented by formula (IV)

wherein X is as defined above, and R₂ represents hydrogen, an optionallysubstituted alkyl group having from 1 to 10 carbon atoms, an optionallysubstituted aryl group having from 6 to 15 carbon atoms, an optionallysubstituted aralkyl group having from 7 to 20 carbon atoms, atrialkylsilyl group having from 3 to 10 carbon atoms, aphenyldialkylsilyl group having 8 to 10 carbon atoms or adiphenylalkylsilyl group having 13 to 15 carbon atoms, to form a4-amino-3-oxo-2-halogenobutanoic acid ester or salt derivativerepresented by formula (III′)

wherein R_(s), P₁, P₂, and X are as defined above, and R₃ representsalkali metal, an optionally substituted alkyl group having from 1 to 10carbon atoms, an optionally substituted aryl group having from 6 to 15carbon atoms, an optionally substituted aralkyl group having from 7 to20 carbon atoms, a trialkylsilyl group having from 3 to 10 carbon atoms,a phenyldialkylsilyl group having 8 to 10 carbon atoms or adiphenylalkylsilyl group having 13 to 15 carbon atoms; (ii) furtherhydrolyzing said compound of formula (III′), to obtain a hydrolyzate;and (iii) decarboxylating said hydrolyzate, to obtain said compound offormula (V).
 5. The process of claim 4, wherein the carbon atom to whichR_(s) is bonded in the compound of formula (I) has a S-configurationexcept for a case where R_(s) in formula (I) is hydrogen.
 6. The processof claim 4, wherein the carbon atom to which R_(s) is bonded in thecompound of formula (I) has an R-configuration except for a case whereR_(s) in formula (I) is hydrogen.
 7. A process for preparing a compoundof formula (VI)

wherein R_(s) represents hydrogen, an optionally substituted alkyl grouphaving from 1 to 10 carbon atoms, an optionally substituted aryl grouphaving from 6 to 15 carbon atoms, an optionally substituted aralkylgroup having from 7 to 20 carbon atoms, or the above-mentioned groupscontaining a hetero atom in the carbon skeleton; P₁ and P₂,independently from each other, represent hydrogen or an amino-protectinggroup, or P₁ and P₂ together form a difunctional amino-protecting group,and at least one of P₁ and P₂ is not hydrogen; and X represents ahalogen atom other than fluorine or its salt, which comprises: (i)reacting a compound represented by formula (I)

wherein R_(s), P₁, and P₂ are as defined, and E₁ represents an alkoxyester residue having from 1 to 10 carbon atoms, a phenoxy or benzyloxygroup, which may have a substituent in the ring, an ester residue ofN-oxysuccinimide or 1-oxybenzotriazole, an active thioester residue, animidazolyl group or a residue capable of forming an acid halide, an acidanhydride or an acid azido, with an alkali metal enolate of an acetateto obtain a compound represented by formula (II)

wherein R_(s), P₁, and P₂ are as defined above, and R₁ represents anoptionally substituted alkyl group having from 1 to 10 carbon atoms, anoptionally substituted aryl group having from 6 to 15 carbon atoms, anoptionally substituted aralkyl group having from 7 to 20 carbon atoms, atrialkylsilyl group having from 4 to 10 carbon atoms, aphenyldialkylsilyl group having 8 to 10 carbon atoms or adiphenylalkylsilyl group having 13 to 15 carbon atoms; (ii) reacting thecompound of formula (II) with a halogenating agent for halogenation ofthe 2-position to form a 4-amino-3oxo-2-halogenobutanoic acid esterderivative represented by formula (III)

wherein R_(s), P₁, P₂, R₁, and X are as defined above; (iii) furtherhydrolyzing the resulting compound of formula (III), to obtain ahydrolyzate; (iv) decarboxylating said hydrolyzate, to obtain a compoundof formula (V)

wherein: R_(s), P₁, P₂, and X are as defined above; and (v) reducingsaid compound of formula (V), to obtain said compound of formula (VI).8. The process of claim 7, wherein the carbon atom to which R_(s) isbonded in the compound of formula (I) has a S-configuration except for acase where R_(s) in formula (I) is hydrogen.
 9. The process of claim 7,wherein the carbon atom to which R_(s) is bonded in the compound offormula (I) has an R-configuration except for a case where R_(s) informula (I) is hydrogen.
 10. A process for producing a compoundrepresented by formula (VI)

wherein R_(s) represents hydrogen, an optionally substituted alkyl grouphaving from 1 to 10 carbon atoms, an optionally substituted aryl grouphaving from 6 to 15 carbon atoms, an optionally substituted aralkylgroup having from 7 to 20 carbon atoms, or the above-mentioned groupscontaining a hetero atom in the carbon skeleton; P₁ and P₂,independently from each other, represent hydrogen or an amino-protectinggroup, or P₁ and P₂ together form a difunctional amino-protecting group,and at least one of P₁ and P₂ is not hydrogen; and X represents ahalogen atom other than fluorine or its salt, which comprises: (i)reacting a compound represented by formula (I)

wherein R₁, P₁, and P₂ are as defined above, and E₁ represents an alkoxyester residue having from 1 to 10 carbon atoms, a phenoxy or benzyloxygroup, which may have a substituent in the ring, an ester residue ofN-oxysuccinimide or 1-oxybenzotriazole, an active thioester residue, animidazolyl group or a residue capable of forming an acid halide, an acidanhydride or an acid azido, with an alkali metal enolate or dianion of acompound represented by formula (IV)

wherein X is as defined above; and R₂ represents hydrogen, an optionallysubstituted alkyl group having from 1 to 10 carbon atoms, an optionallysubstituted aryl group having from 6 to 15 carbon atoms, an optionallysubstituted aralkyl group having from 7 to 20 carbon atoms, atrialkylsilyl group having from 3 to 10 carbon atoms, aphenyldialkylsilyl group having 8 to 10 carbon atoms or adiphenylalkylsilyl group having 13 to 15 carbon atoms; to form a4-amino-3oxo-2-halogenobutanoic acid ester derivative represented byformula (III′)

wherein R_(s), P₁, P₂, and X are as defined above; and R₃ representsalkali metal, an optionally substituted alkyl group having from 1 to 10carbon atoms, an optionally substituted aryl group having from 6 to 15carbon atoms, an optionally substituted aralkyl group having from 7 to20 carbon atoms, a trialkylsilyl group having from 3 to 10 carbon atoms,a phenyldialkylsilyl group having 8 to 10 carbon atoms or adiphenylalkylsilyl group having 13 to 15 carbon atoms; (iii) furtherhydrolyzing said compound of formula (III′), to obtain a hydrolyzate;(iv) decarboxylating said hydrolyzate, to obtain a compound of formula(V):

wherein: R_(s), P₁, P₂, and X are as defined above; and (v) reducingsaid compound of formula (V), to obtain said compound of formula (VI).11. The process of claim 13 claim 10, wherein the carbon atom to whichR_(s) is bonded in the compound of formula (I) has a S-configurationexcept for a case where R_(s) in formula (I) is hydrogen.
 12. Theprocess of claim 13 claim 10, wherein the carbon atom to which R_(s) isbonded in the compound of formula (I) has an R-configuration except fora case where R_(s) in formula (I) is hydrogen.
 13. A process forpreparing a compound of formula (VII)

wherein R_(s) represents hydrogen, an optionally substituted alkyl grouphaving from 1 to 10 carbon atoms, an optionally substituted aryl grouphaving from 6 to 15 carbon atoms, an optionally substituted aralkylgroup having from 7 to 20 carbon atoms, or the above-mentioned groupscontaining a hetero atom in the carbon skeleton; and P₁ and P₂,independently from each other, represent hydrogen or an amino-protectinggroup, or P₁ and P₂ together form a difunctional amino-protecting group,and at least one of P₁ and P₂ is not hydrogen; or its salt, whichcomprises: (i) reacting a compound represented by formula (I)

wherein R_(s), P₁ and P₂ are as defined above, and E₁ represents analkoxy ester residue having from 1 to 10 carbon atoms, a phenoxy orbenzyloxy group, which may have a substituent in the ring, an esterresidue of N-oxysuccinimide or 1-oxybenzotriazole, an active thioesterresidue, an imidazolyl group or a residue capable of forming an acidhalide, an acid anhydride or an acid azido, with an alkali metal enolateof an acetate to obtain a compound represented by formula (II)

wherein R_(s), P₁, and P₂ are as defined above, and R₁ represents anoptionally substituted alkyl group having from 1 to 10 carbon atoms, anoptionally substituted aryl group having from 6 to 15 carbon atoms, anoptionally substituted aralkyl group having from 7 to 20 carbon atoms, atrialkylsilyl group having from 4 to 10 carbon atoms, aphenyldialkylsilyl group having 8 to 10 carbon atoms or adiphenylalkylsilyl group having 13 to 15 carbon atoms; (ii) reacting thecompound of formula (II) with a halogenating agent for halogenation ofthe 2-position to form a 4-amino-3oxo-2-halogenobutanoic acid esterderivative represented by formula (III)

wherein R_(s), P₁, P₂, and R₁ are as defined above; and X is a halogenatom other than fluorine; (iii) further hydrolyzing the resultingcompound of formula (III), to obtain a hydrolyzate; (iv) decarboxylatingsaid hydrolyzate, to obtain a compound of formula (V)

wherein: R_(s), P₁, P₂, and X are as defined above; (v) reducing saidcompound of formula (V), to obtain a compound of formula (VI)

wherein R_(s), P₁, P₂, and X are as defined above; and (vi) epoxidizingsaid compound of formula (VI), to obtain said compound of formula (VII).14. The process of claim 13, wherein the carbon atom to which R_(s) isbonded in the compound of formula (I) has a S-configuration except for acase where R_(s) in formula (I) is hydrogen.
 15. The process of claim13, wherein the carbon atom to which R_(s) is bonded in the compound offormula (I) has an R-configuration except for a case where R_(s) informula (I) is hydrogen.
 16. A process for producing a compoundrepresented by formula (VII)

wherein R_(s) represents hydrogen, an optionally substituted alkyl grouphaving from 1 to 10 carbon atoms, an optionally substituted aryl grouphaving from 6 to 15 carbon atoms, an optionally substituted aralkylgroup having from 7 to 20 carbon atoms, or the above-mentioned groupscontaining a hetero atom in the carbon skeleton; P₁ and P₂,independently from each other, represent hydrogen or an amino-protectinggroup, or P₁ and P₂ together form a difunctional amino-protecting group,and at least one of P₁, and P₂ is not hydrogen; or its salt, whichcomprises: (i) reacting a compound represented by formula (I)

wherein R_(s), P₁, and P₂ are as defined above, and E₁ represents analkoxy ester residue having from 1 to 10 carbon atoms, a phenoxy orbenzyloxy group, which may have a substituent in the ring, an esterresidue of N-oxysuccinimide or 1-oxybenzotriazole, an active thioesterresidue, an imidazolyl group or a residue capable of forming an acidhalide, an acid anhydride or an acid azido, with an alkali metal enolateof an acetate to obtain a compound represented by formula (IV)

wherein X is a halogen atom other than fluorine; and R₂ representshydrogen, an optionally substituted alkyl group having from 1 to 10carbon atoms, an optionally substituted aryl group having from 6 to 15carbon atoms, an optionally substituted aralkyl group having from 7 to20 carbon atoms, a trialkylsilyl group having from 3 to 10 carbon atoms,a phenyldialkylsilyl group having 8 to 10 carbon atoms or adiphenylalkylsilyl group having 13 to 15 carbon atoms; to form a4-amino-3oxo-2-halogenobutanoic acid ester derivative represented byformula (III′)

wherein R_(s), P₁, P₂, and X are as defined above; and R₃ representsalkali metal, an optionally substituted alkyl group having from 1 to 10carbon atoms, an optionally substituted aryl group having from 6 to 15carbon atoms, an optionally substituted aralkyl group having from 7 to20 carbon atoms, a trialkylsilyl group having from 3 to 10 carbon atoms,a phenyldialkylsilyl group having 8 to 10 carbon atoms or adiphenylalkylsilyl group having 13 to 15 carbon atoms; (iii) furtherhydrolyzing said compound of formula (III′), to obtain a hydrolyzate;(iv) decarboxylating said hydrolyzate, to obtain a compound of formula(V):

wherein: R_(s), P₁, P₂, and X are as defined above; (v) reducing saidcompound of formula (V), to obtain a compound of formula (VI)

wherein R_(s), P₁, P₂, and X are as defined above; and (vi) epoxidizingsaid compound of formula (VI), to obtain said compound of formula (VII).17. The process of claim 16, wherein the carbon atom to which R_(s) isbonded in the compound of formula (I) has a S-configuration except for acase where R_(s) in formula (I) is hydrogen.
 18. The process of claim16, wherein the carbon atom to which R_(s) is bonded in the compound offormula (I) has an R-configuration except for a case where R_(s) informula (I) is hydrogen.
 19. A process for producing a compoundrepresented by formula (II):

wherein R _(s) represents hydrogen, an optionally substituted alkylgroup having from 1 to 10 carbon atoms, an optionally substituted arylgroup having from 6 to 15 carbon atoms, an optionally substitutedaralkyl group having from 7 to 20 carbon atoms, or the above-mentionedgroups containing a hetero atom in the carbon skeleton; P ₁ and P ₂ ,independently from each other, represent hydrogen or an amino-protectinggroup, or P ₁ and P ₂ together form a difunctional amino-protectinggroup, and at least one of P ₁ and P ₂ is not hydrogen; and R ₁represents an optionally substituted alkyl group having from 1 to 10carbon atoms, an optionally substituted aryl group having from 6 to 15carbon atoms, an optionally substituted aralkyl group having from 7 to20 carbon atoms, a trialkylsilyl group having from 4 to 10 carbon atoms,a phenyldialkylsilyl group having 8 to 10 carbon atoms or adiphenylalkylsilyl group having 13 to 15 carbon atoms; which processcomprises reacting a compound represented by formula (I):

wherein R _(s) , P ₁ , and P ₂ are as defined above; and E ₁ representsan alkoxy ester residue having from 1 to 10 carbon atoms, a phenoxy orbenzyloxy group which may have a substituent in the ring; with an alkalimetal enolate of an acetate.
 20. The process of claim 19, wherein thecarbon atom to which R_(s) is bonded in the compound of formula (I) hasan S-configuration except for a case where R _(s) in formula (I) ishydrogen.
 21. The process of claim 19, wherein the carbon atom to whichR_(s) is bonded in the compound of formula (I) has an R-configurationexcept for a case where R _(s) in formula (I) is hydrogen.
 22. Theprocess of claim 19, wherein R₁ represents an optionally substitutedalkyl group having from 1 to 10 carbon atoms, an optionally substitutedaryl group having from 6 to 15 carbon atoms, or an optionallysubstituted aralkyl group having from 7 to 20 carbon atoms.